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β-Caryophyllene (BCP), a dietary phytocannabinoid, significantly suppresses palmitate-induced lipid accumulation in human HepG2 hepatocytes via activation of AMP-activated protein kinase (AMPK) signaling. The objective of the preset research was to assess whether oral administration of BCP alleviates obesity-induced hepatic steatosis in mice through AMPK activation. We examined the protective action of supplementation of 0.3% BCP (w/w) in a high-fat diet (HFD) on C57BL/6J mice for 12 weeks. BCP supplementation evidently ameliorated histological hepatic steatosis features, and significantly reduced triglycerides and cholesterol levels in the liver, and serum levels of aspartate aminotransferase and alanine aminotransferase as compared with non-supplemented HFD-fed mice. Immunoblotting revealed that BCP supplementation in HFD-fed mice also caused hepatic AMPK activation. Furthermore, treatment with BCP in HFD-fed mice significantly suppressed body weight gain and attenuated obesity-related phenotypes relative to the HFD mice. Our results suggest the usefulness of BCP in the prevention of obesity-related liver steatosis and liver injury., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Nonalcoholic fatty liver disease (NAFLD) causes significant global mortality and healthcare costs with no recommended pharmacological intervention for clinical management. Nuciferine (Nuc) is an alkaloid with aromatic rings, abundantly found in Nelumbo nucifera Gaertn . In this study, we explored the protective mechanisms of Nuc against hepatic steatosis and ferroptosis in NAFLD. High-fat diet (HFD) and healthy male ApoE -/- mice were used to induce NAFLD and a hypercholesterolemia model. Nuc was administered to the mice for four consecutive weeks from the ninth week. Various assessments, including histopathology, RNA sequencing, lipid metabolism, and ferroptosis-related protein expression, showed that Nuc alleviated hepatic steatosis and ferroptosis. We further showed that Nuc improves fatty acid accumulation and ferroptosis through the PPARα signaling pathway in mice and RSL3-treated AML-12 cells. The PPARα inhibitor GW6471 blocked Nuc's protective effects, leading to excess accumulation of iron ions. Thus, Nuc may be a potential therapeutic agent for NAFLD.

Scope: The gut microbiota plays a role in fat accumulation and energy homeostasis. Therefore, probiotic supplementation may improve metabolic parameters and control body weight., Methods and Results: In this study, mice are fed either a high-fat diet (HFD) or an HFD supplemented with oral gavage of a mixture of three probiotic strains, Bifidobacterium lactis Lafti B94, Lactobacillus plantarum HA-119, and Lactobacillus helveticus Lafti L10 for 7 weeks. It finds that probiotic supplementation modulates body weight gain, food energy efficiency, and fat accumulation caused by the HFD. This probiotic mix prevents liver damage and lipid metabolic disorders in HFD-fed obese mice. The probiotic supplementation significantly downregulates the expression of the proinflammatory cytokines interleukin-1β, tumor necrosis factor-α, and malondialdehyde (MDA) in the liver and upregulated catalase (CAT), superoxide dismutase (SOD), and nuclear respiratory factor 1 (Nrf1) expression. Mice supplemented with the probiotic mix also show different microbiota compositions, with an increase in Clostridia_UCG-014 and Lachnospiraceae_nk4a136_group and a decrease in the Dubosiella genus compared with those in mice fed only an HFD. Finally, the amounts of fecal pentanoic acid and the three bile acid species increase in mice with probiotic supplementation., Conclusion: Treatment with a combination of a mixture of three probiotic strains, B. lactis Lafti B94, L. plantarum HA-119, and L. helveticus Lafti L10 for 7 weeks, ameliorates the effects of HFD induced obesity in mice., (© 2024 Wiley‐VCH GmbH.)

Metabolic diseases that include obesity and metabolic-associated fatty liver disease (MAFLD) are a rapidly growing worldwide public health problem. The pathogenesis of MAFLD includes abnormally increased lipogenesis, chronic inflammation, and mitochondrial dysfunction. Mounting evidence suggests that hydrogen sulfide (H 2 S) is an important player in the liver, regulating lipid metabolism and mitochondrial function. However, direct delivery of H 2 S to mitochondria has not been investigated as a therapeutic strategy in obesity-related metabolic disorders. Therefore, our aim was to comprehensively evaluate the influence of prolonged treatment with a mitochondria sulfide delivery molecule (AP39) on the development of fatty liver and obesity in a high fat diet (HFD) fed mice. Our results demonstrated that AP39 reduced hepatic steatosis in HFD-fed mice, which was corresponded with decreased triglyceride content. Furthermore, treatment with AP39 downregulated pathways related to biosynthesis of unsaturated fatty acids, lipoprotein assembly and PPAR signaling. It also led to a decrease in hepatic de novo lipogenesis by downregulating mTOR/SREBP-1/SCD1 pathway. Moreover, AP39 administration alleviated obesity in HFD-fed mice, which was reflected by reduced weight of mice and adipose tissue, decreased leptin levels in the plasma and upregulated expression of adipose triglyceride lipase in epididymal white adipose tissue (eWAT). Finally, AP39 reduced inflammation in the liver and eWAT measured as the expression of proinflammatory markers (Il1b, Il6, Tnf, Mcp1), which was due to downregulated mTOR/NF-κB pathway. Taken together, mitochondria-targeted sulfide delivery molecules could potentially provide a novel therapeutic approach to the treatment/prevention of obesity-related metabolic disorders., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Mark E. Wood, Roberta Torregrossa, Matthew Whiteman has patent pending to slow-release sulfide-generating molecules and their therapeutic use. Matthew Whiteman is CSO of MitoRx Therapeutics, Oxford, U.K, developing organelle-targeted molecules for clinical use. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Metabolic dysfunction-associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including hyperglycemia, hepatic steatosis, and insulin resistance. Piperlongumine (PL), a natural amide alkaloid extracted from the fruits of Piper longum L., exhibited hepatoprotective effects in zebrafish and liver injury mice. This study aimed to investigate the therapeutic potential of PL on MAFLD and its underlying mechanisms. The findings demonstrate that PL effectively combats MAFLD induced by a high-fat diet (HFD) and improves metabolic characteristics in mice. Additionally, our results suggest that the anti-MAFLD effect of PL is attributed to the suppression of excessive hepatic gluconeogenesis, inhibition of de novo lipogenesis, and alleviation of insulin resistance. Importantly, the results indicate that, on the one hand, the hypoglycemic effect of PL is closely associated with CREB-regulated transcriptional coactivators (CRTC2)-dependent cyclic AMP response element binding protein (CREB) phosphorylation; on the other hand, the lipid-lowering effect of PL is attributed to reducing the nuclear localization of sterol regulatory element-binding proteins 1c (Srebp-1c). Mechanistically, PL could alleviate insulin resistance induced by endoplasmic reticulum stress by antagonizing the thromboxane A 2 receptor (TP)/Ca 2+ signaling, and the TP receptor serves as the potential target for PL in the treatment of MAFLD. Therefore, our results suggested PL effectively improved the major hallmarks of MAFLD induced by HFD, highlighting a potential therapeutic strategy for MAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: To assess the effects of a small-molecule nicotinamide N-methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet-induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo., Materials and Methods: DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age- and strain-matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ., Results: 5A1MQ treatment dose-dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ-treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice., Conclusions: This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity., (© 2024 John Wiley & Sons Ltd.)

The purpose of this study is to investigate the mechanism by which 6-shogaol ameliorates hepatic steatosis via miRNA-mRNA interaction analysis. C57BL/6 J mice were fed a high-fat diet (HFD) for 12 weeks, during which 6-shogaol was administered orally. The liver lipid level, liver function and oxidative damage in mice were evaluated. mRNA sequencing, miRNA sequencing, and RT-qPCR were employed to compare the expression profiles between the HFD group and the 6-shogaol-treated group. High-throughput sequencing was used to construct the mRNA and miRNA libraries. Target prediction and integration analysis identified eight potential miRNA-mRNA pairs involved in hepatic steatosis, which were subsequently validated in liver tissues and AML12 cells. The findings revealed that 6-shogaol modulates the miR-3066-5p/Grem2 pathway, thereby improving hepatic steatosis. This study provides new insights into the mechanisms through which 6-shogaol alleviates hepatic steatosis, establishing a foundation for future research on natural active compounds for the treatment of metabolic diseases., Competing Interests: Declaration of competing interest All authors of this work have no relevant conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Several Previous studies indicate that consuming krill oil may aid in reducing hypercholesterolemia and improving cholesterol metabolism. Therefore, our study was designed to investigate the effectiveness of Antarctic krill oil ( Euphausia superba ) (ESKO) in combating obesity and lowering fat/lipid/cholesterol levels., Methods: The study aimed to investigate the molecular docking model targeting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) using ESKO-derived eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and astaxanthin. In this study, histological alterations in the liver of the obesity model (ICR male mouse), obesity-related or antioxidant markers in both liver and serum, the molecular mechanisms in HepG2 cells and liver tissue, and HMGCR activity were analyzed., Results: Our findings revealed that a high-fat diet (HFD) significantly led to increased oxidative stress, obesity-related indicators, and cardiovascular-associated risk indices. However, ESKO effectively mitigated HFD-induced oxidative stress, fat accumulation, and the suppression of low-density lipoprotein receptor (LDLR) or activation of related molecular pathways. This was achieved through improvements in metabolic parameters, including CD36/liver X receptor α (LXRα)/sterol regulatory element-binding protein 1c (SREBP1c), proprotein convertase subtilsin/kexin type 9 (PCSK-9), and HMGCR, ultimately ameliorating HFD-induced hypercholesterolemia and obesity., Conclusions: These beneficial findings indicate that ESKO might have significant potential for preventing and treating obesity-related disorders.

Background and Aims: Metabolic liver disease is associated with obesity, insulin resistance, cardiovascular disease, and metabolic disorders. A Mediterranean diet (MD), known for its anti-inflammatory and antioxidant properties, is effective in managing various chronic diseases, including liver diseases. This study aimed to explore the influence of adherence to the MD on the risk of chronic metabolic diseases, including steatotic liver disease (SLD), metabolic dysfunction-associated steatotic liver disease (MASLD), and alcohol-related liver diseases (ALDs)., Methods: This retrospective cohort study analyzed 5395 individuals from a single center between 2020 and 2022, grouped by adherence to the MD using the Korean Mediterranean Diet Adherence Score (K-MEDAS). MASLD score, ALD, and cardiovascular risk factors were also assessed. Statistical analyses were performed using 1:1 exact matching and multiple regression to compare the less adherent (K-MEDAS 0-7) and highly adherent (K-MEDAS 8-13) groups., Results: Adjusting for confounding variables, high adherence to the MD was significantly associated with lower rates of SLD (odds ratio [OR] 0.818, 95% confidence interval [CI] 0.700-0.957, p = 0.012), MASLD (OR 0.839, 95% CI 0.714-0.986, p = 0.033), and ALD (OR 0.677, 95% CI 0.671-0.683, p < 0.001). Post-propensity score matching analysis revealed that the highly adherent group exhibited significantly lower triglyceride levels, triglyceride and glucose index, atherogenic Index of Plasma, and Framingham risk scores than the less adherent group., Conclusions: Good adherence to the MD considerably reduces the risk of SLD, MASLD, and ALD, underscoring its protective effects and potential to prevent metabolic liver diseases and their complications.

The production of the omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from alpha-linolenic acid (ALA) relies on the delta-6 desaturase (D6D) enzyme encoded by the Fads2 gene. While EPA and DHA reduce hepatic triacylglycerol (TAG) storage and regulate lipogenesis, the independent impact of ALA is less understood. To address this gap in knowledge, hepatic fatty acid metabolism was investigated in male wild-type (WT) and Fads2 knockout (KO) mice fed diets (16% kcal from fat) containing either lard (no n-3 LCPUFA), flaxseed oil (ALA-rich), or menhaden oil (EPA/DHA rich) for 21 weeks. Fat content and composition, as well as markers of lipogenesis, glyceroneogenesis, and TAG synthesis, were analyzed using histology, gas chromatography, and reverse transcription quantitative PCR (RT-qPCR). Mice fed the menhaden diet had significantly lower hepatic TAG compared to both lard- and flax-fed mice, concomitant with changes in n-3 and n-6 LCPUFA in both TAG and phospholipid (PL) fractions (all P < 0.05). Flax-fed WT mice had lower liver TAG content compared to their KO counterparts. Menhaden-fed mice had significantly lower expression of key lipogenic (Scd1, Srebp-1c, Fasn, Fads1, and Fads2), glyceroneogenic (Pck1), and TAG synthesis (Agpat3) genes compared to lard, with flax-fed mice showing some intermediate effects. Gene expression effects were independent of D6D activity, since no differences were detected between WT and KO mice fed the same diet. This study demonstrates that EPA/DHA and not ALA itself is critical for the prevention of hepatic steatosis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Intravenous lipid emulsions used in preterm infants contain insufficient docosahexaenoic acid (DHA) and arachidonic acid (ARA) to support normal development, resulting in deficiencies that contribute to complications of prematurity and cognitive delay. We sought to investigate the effects of new intravenous lipid emulsions designed to contain sufficient DHA and ARA to meet preterm needs, while avoiding liver toxicity., Methods: Three new lipid emulsions (NLE A-C) were laboratory-generated using high pressure homogenization. First, a long-term experiment evaluated the impact on plasma, liver, and frontal cortex fatty acid composition compared to commercially available lipid emulsions. Lipid emulsions were administered via daily orogastric gavage to four-week-old C57Bl/6 J mice. Next, liver toxicity was evaluated in a murine model of parenteral nutrition-induced hepatosteatosis. Mice were provided an ad lib fat-free high carbohydrate diet, with intravenous lipid emulsion administration every other day for 19 days., Results: Administration of commercially available lipid emulsions (soybean oil, mixed oil, or fish oil) resulted in decreased plasma and tissue levels of DHA and/or ARA compared to a chow control. The new lipid emulsions demonstrated a dose-response effect in plasma and tissue concentration of DHA and ARA. NLE C (with an approximately even DHA:ARA ratio), compared to chow, maintained similar DHA (19.2 ± 0.3 vs. 19.3 ± 0.3%, P = 1.00) and ARA (10.4 ± 0.2 vs. 9.9 ± 0.2% ARA, P = 0.75) content in frontal cortex tissue. All three new lipid emulsions prevented biochemical liver injury and pathologist-assessed hepatosteatosis; soybean oil lipid emulsion and mixed oil lipid emulsion treatment resulted in hepatosteatosis in both experiments., Conclusion: Long-term treatment with the new lipid emulsions in juvenile mice resulted in increased plasma and tissue DHA and/or ARA content compared to currently available lipid emulsions. The new lipid emulsions also prevented hepatosteatosis and biochemical liver injury with enteral and parenteral administration., Competing Interests: Conflict of Interest statement A patent application has been filed by SF, KG, and MP entitled “Methods and Compositions Relating to Treatment and Prevention of Fatty Acid Deficiencies.” KG and MP also hold a patent related to the use of fish oil lipid emulsion for the treatment of parenteral nutrition-associated cholestasis., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 20%-30% of the general population and is linked to high-caloric western style diet. However, there are little data that specific nutrients might help to prevent steatosis., Methods: We analysed the UK Biobank (ID 71300) 24 h-nutritional assessments and investigated the association between nutrient intake calculated from food questionnaires and hepatic steatosis indicated by imaging or ICD10-coding. The effect of manganese (Mn) on subgroups with risk single nucleotide polymorphism carriage as well as the effect on metabolomics was investigated. All analyses are corrected for age, sex, body mass index, Townsend index for socioeconomic status, kcal, alcohol, protein intake, fat intake, carbohydrate intake, energy from beverages, diabetes, physical activity and for multiple testing., Results: We used a random forest classifier to analyse the feature importance of 63 nutrients and imaging-proven steatosis in a cohort of over 25 000 UK Biobank participants. Increased dietary Mn intake was associated with a lower likelihood of MRI-diagnosed steatosis. Subsequently, we conducted a cohort study in over 200 000 UK Biobank participants to explore the relationship between Mn intake and hepatic or cardiometabolic outcomes and found that higher Mn intake was associated with a lower risk of ICD-10 coded steatosis (OR = .889 [.838-.943], p < .001), independent of other potential confounders., Conclusion: Our study provides evidence that higher Mn intake may be associated with lower odds of steatosis in a large population-based sample. These findings underline the potential role of Mn in the prevention of steatosis, but further research is needed to confirm these findings and to elucidate the underlying mechanisms., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Purpose: Tamoxifen, a widely used drug for breast cancer treatment, is associated with adverse effects on the liver, including the development of fatty liver. This study aimed to investigate the potential protective effect of caffeine against tamoxifen-induced fatty liver in Wistar rats., Methods: Rats were divided into normal control, tamoxifen + saline, and tamoxifen + caffeine. Plasma samples were assessed for biochemical markers related to oxidative stress, inflammation, liver function, and cell damage. Additionally, liver histopathology was examined to quantify the extent of fatty infiltration., Results: In the tamoxifen + saline group, elevated levels of plasma malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), alanine aminotransferase (ALT), cytokeratin 18, and soluble ST2 were observed compared to the normal control group, indicating increased oxidative stress, inflammation, and liver injury (p < 0.01). Moreover, histopathological examination revealed a significant increase in fatty infiltration (p < 0.001). However, in the tamoxifen + caffeine group, these markers were markedly reduced (p < 0.05, p < 0.01), and fatty infiltration was significantly mitigated (p < 0.001)., Conclusions: The findings suggest that caffeine administration attenuates tamoxifen-induced fatty liver in rats by ameliorating oxidative stress, inflammation, liver injury, and cell damage. Histopathological evidence further supports the protective role of caffeine. This study highlights the potential of caffeine as a therapeutic intervention to counter tamoxifen-induced hepatic complications, contributing to the optimization of breast cancer treatment strategies.

Metabolic dysfunction-associated steatotic liver disorder (MASLD) is increasingly prevalent globally, highlighting the need for preventive strategies and early interventions. This comprehensive review explores the potential of health functional foods (HFFs) to maintain healthy liver function and prevent MASLD through an integrative analysis of network pharmacology, gut microbiota, and multi-omics approaches. We first examined the biomarkers associated with MASLD, emphasizing the complex interplay of genetic, environmental, and lifestyle factors. We then applied network pharmacology to identify food components with potential beneficial effects on liver health and metabolic function, elucidating their action mechanisms. This review identifies and evaluates strategies for halting or reversing the development of steatotic liver disease in the early stages, as well as biomarkers that can evaluate the success or failure of such strategies. The crucial role of the gut microbiota and its metabolites for MASLD prevention and metabolic homeostasis is discussed. We also cover state-of-the-art omics approaches, including transcriptomics, metabolomics, and integrated multi-omics analyses, in research on preventing MASLD. These advanced technologies provide deeper insights into physiological mechanisms and potential biomarkers for HFF development. The review concludes by proposing an integrated approach for developing HFFs targeting MASLD prevention, considering the Korean regulatory framework. We outline future research directions that bridge the gap between basic science and practical applications in health functional food development. This narrative review provides a foundation for researchers and food industry professionals interested in developing HFFs to support liver health. Emphasis is placed on maintaining metabolic balance and focusing on prevention and early-stage intervention strategies.

The mitochondrial citrate shuttle, which relies on the solute carrier family 25 member 1 (SLC25A1), plays a pivotal role in transporting citrate from the mitochondria to the cytoplasm. This shuttle supports glycolysis, lipid biosynthesis, and protein acetylation. Previous research has primarily focused on SLC25A1 in pathological models, particularly high-fat diet (HFD)-induced obesity. However, the impact of SLC25A1 inhibition on nutrient metabolism under HFD remains unclear. To address this gap, we used zebrafish ( Danio rerio ) and Nile tilapia ( Oreochromis niloticus ) to evaluate the effects of inhibiting Slc25a1. In zebrafish, we administered Slc25a1-specific inhibitors (CTPI-2) for 4 wk, whereas Nile tilapia received intraperitoneal injections of dsRNA to knock down slc25a1b for 7 days. Inhibition of the mitochondrial citrate shuttle effectively protected zebrafish from HFD-induced obesity, hepatic steatosis, and insulin resistance. Of note, glucose tolerance was unaffected. Inhibition of Slc25a1 altered hepatic protein acetylation patterns, with decreased cytoplasmic acetylation and increased mitochondrial acetylation. Under HFD conditions, Slc25a1 inhibition promoted fatty acid oxidation and reduced hepatic triglyceride (TAG) accumulation by deacetylating carnitine palmitoyltransferase 1a (Cpt1a). In addition, Slc25a1 inhibition triggered acetylation-induced inactivation of Pdhe1α, leading to a reduction in glucose oxidative catabolism. This was accompanied by enhanced glucose uptake and storage in zebrafish livers. Furthermore, Slc25a1 inhibition under HFD conditions activated the SIRT1/PGC1α pathway, promoting mitochondrial proliferation and enhancing oxidative phosphorylation for energy production. Our findings provide new insights into the role of nonhistone protein acetylation via the mitochondrial citrate shuttle in the development of hepatic lipid deposition and hyperglycemia caused by HFD. NEW & NOTEWORTHY The mitochondrial citrate shuttle is a crucial physiological process for maintaining metabolic homeostasis. In the present study, we found that inhibition of mitochondrial citrate shuttle (Slc25a1) could alleviate metabolic syndromes induced by high-fat diet (HFD) through remodeling hepatic protein acetylation modification. Briefly, Slc25a1 inhibition reduces hepatic triglyceride deposition by deacetylating Cpt1a and reduces glucose oxidative catabolism by acetylating Pdhe1α. Our study provides new insights into the treatment of diet-induced metabolic syndromes.

Drug-resistant epilepsy patients may benefit from non-pharmacological therapies, such as the ketogenic diet (KD). However, its high fat content poses compliance challenges and metabolic risks. To mitigate this, we developed a novel KD composition with less fat and additional nutrients (citrate, nicotinamide riboside, and omega-3 fatty acids) for ketone-independent neuroprotection. The efficacy, metabolic and neuropathological effects of the novel KD and a classic KD were compared to a control diet in the rapid kindling model of temporal lobe epilepsy. Both KD groups entered ketosis before kindling onset, with higher ketone levels in the classic KD group. Remarkably, rats on the novel KD had slower progression of behavioral seizures as compared to rats on a control diet, while this was not the case for rats on a classic KD. Both KDs reduced electrographic after-discharge duration, preserved neurons in the dorsal hippocampus, and normalized activity in open field tests. The novel KD, despite lower fat and ketone levels, demonstrated effective reduction of behavioral seizure severity while the classic KD did not, suggesting alternative mode(s) of action are involved. Additionally, the novel KD significantly mitigated liver triglyceride and plasma fatty acid levels compared to the classic KD, indicating a reduced risk of long-term liver steatosis. Our findings highlight the potential of the novel KD to enhance therapeutic efficacy and compliance in epilepsy patients., Competing Interests: Declaration of competing interest H. Meeusen, J.P. Silva, J.M. Verkuyl and A. van Helvoort were under employment by Danone Nutricia Research during this study. The remaining authors have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Dietary medium-chain fatty acids (MCFAs), characterized by chain lengths of 8-12 carbon atoms, have been proposed to have beneficial effects on glucose and lipid metabolism, yet the underlying mechanisms remain elusive. We hypothesized that MCFA intake benefits metabolic health by inducing the release of hormone-like factors., Methods: The effects of chow diet, high-fat diet rich in long-chain fatty acids (LCFA HFD) fed ad libitum or pair-fed to a high-fat diet rich in MCFA (MCFA HFD) on glycemia, hepatic gene expression, circulating fibroblast growth factor 21 (FGF21), and liver fat content in both wildtype and Fgf21 knockout mice were investigated. The impact of a single oral dose of an MCFA-rich oil on circulating FGF21 and hepatic Fgf21 mRNA expression was assessed. In flag-tagged Crebh knockin mice and liver-specific Crebh knockout mice, fed LCFA HFD or MCFA HFD, active hepatic CREBH and hepatic Fgf21 mRNA abundance were determined, respectively., Results: MCFA HFD improves glucose tolerance, enhances glucose clearance into brown adipose tissue, and prevents high-fat diet-induced hepatic steatosis in wildtype mice. These benefits are associated with increased liver expression of CREBH target genes (Apoa4 and Apoc2), including Fgf21. Both acute and chronic intake of dietary MCFAs elevate circulating FGF21. Augmented hepatic Fgf21 mRNA following MCFA HFD intake is accompanied by higher levels of active hepatic CREBH; and MCFA-induced hepatic Fgf21 expression is blocked in mice lacking Crebh. Notably, while feeding male and female Fgf21 wildtype mice MCFA HFD results in reduced liver triacylglycerol (TG) levels, this liver TG-lowering effect is blunted in Fgf21 knockout mice fed MCFA HFD. The reduction in liver TG levels observed with MCFA HFD was independent of weight loss., Conclusions: Dietary MCFAs reduce liver fat accumulation via activation of a CREBH-FGF21 signaling axis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.C. is co-founder of Ousia Pharma ApS, a biotech company developing therapeutics for obesity. C.C. is also on the editorial board of Molecular Metabolism. The remaining authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

The flower of Gomphrena globosa (G. globosa.) is used as Chinese traditional medicine and functional food. Extractions from G. globosa. have been reported to exert hepatoprotective effects. We further hypothesized that the polysaccharide components, as a bioactive ingredient, might have anti-fatty and hepatitis function. Here, a novel homogeneous arabinoglucan GGL0.05S1 (Mw = 83.9 kDa) from this flower, was characterized by monosaccharide composition analysis, methylation analysis, and NMR. Structural analysis showed that the backbone of GGL0.05S1 consists of →4)-α-Glcp-(1→ and →4,6)-α-Glcp-(1→ residues, and the branched chain linked to the main chain via C-6 of →4,6)-α-Glcp-(1→ in the form α-Araf-(1→[4)-α-Glcp-(1] b → (b > 2). In vitro experiments demonstrated that GGL0.05S1 could inhibit lipid deposition and ROS overload in free fatty acid-induced hepatocytes, meanwhile in vivo tests showed that GGL0.05S1 effectively protected against liver injury, steatohepatitis, and fibrosis in a CDA-HFD-fed MASH model. Mechanism study further uncovered that GGL0.05S1 augmented the expression and antioxidant ability of thioredoxin protein that ameliorated oxidative stress, promoted fatty acid β-oxidation and mitophagy, up to reducing lipotoxicity and alleviating inflammation via inhibiting NLRP3 signaling pathway. Overall, GGL0.05S1 might be a potential novel active compound with liver-protective effect from G. globosa., and which is informative for anti-MASH new drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: This study compared the ability of Liquorice roots aqueous extract (LRE) and its ingredient, isoliquiritigenin (ISL), in alleviating high-fat diet (HFD)-induced hepatic steatosis and examined if this effect involves activation of AMPK. Materials and methods: Control or HFD-fed rats were treated with the vehicle, LRE (200 mg/kg), or ISL (30 mg/kg) for 8 weeks orally. Results: ISL and LRE reduced HFD-induced hyperglycaemia, improved liver structure, lowered serum and hepatic lipids, and attenuated hepatic oxidative stress and inflammation. In the control and HFD-fed rats, ISL and LRE significantly stimulated the muscular and hepatic mRNA and protein levels of AMPK, improved oral glucose tolerance, reduced hepatic mRNA levels of SREBP1/2, and upregulated hepatic levels of PPARα and Bcl2. These effects were comparable for ISL and LRE and were prevented by co-administration of compound C, an AMPK inhibitor. Discussion and conclusion: ISL and LRE provide an effective theory to alleviate hepatic steatosis through activating AMPK.

Mitochondria can contact lipid droplets (LDs) to form peridroplet mitochondria (PDM) which trap fatty acids in LDs by providing ATP for triglyceride synthesis and prevent lipotoxicity. However, the role of PDM in metabolic dysfunction associated steatotic liver disease (MASLD) is not clear. Here, the features of PDM in dietary MASLD models with different severity in mice were explored. Electron microscope photographs show that LDs and mitochondria rarely come into contact with each other in normal liver. In mice fed with high-fat diet, PDM can be observed in the liver as early as the beginning of steatosis in hepatocytes. For the first time, we show that PDM in mouse liver varies with the severity of MASLD. PDM and cytosolic mitochondria were isolated from the liver tissue of MASLD and analyzed by quantitative proteomics. Compared with cytosolic mitochondria, PDM have enhanced mitochondrial respiration and ATP synthesis. Diethyldithiocarbamate (DDC) alleviates choline-deficient, L-amino acid-defined diet-induced MASLD, while increases PDM in the liver. Similarly, DDC promotes the contact of mitochondria-LDs in steatotic C3A cells in vitro. Meanwhile, DDC promotes triglyceride synthesis and improves mitochondrial dysfunction in MASLD. In addition, DDC upregulates perilipin 5 both in vivo and in vitro, which is considered as a key regulator in PDM formation. Knockout of perilipin 5 inhibits the contact of mitochondria-LDs induced by DDC in C3A cells. These results demonstrate that PDM might be associated with the progression of MASLD and the prevention of MASLD by DDC., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Algal polysaccharides possess many biological activities and health benefits, such as antioxidant, anti-tumor, anti-coagulant, and immunomodulatory potential. Gut microbiota has emerged as one of the major contributor in mediating the health benefits of algal polysaccharides. In this study we showed that Haematococcus pluvialis polysaccharides (HPP) decreased serum transaminase levels and hepatic triglyceride content, alleviated inflammation and oxidative stress in the liver of chronic and binge ethanol diet-fed mice. Furthermore, HPP reduced endotoxemia, improved gut microbiota dysbiosis, inhibited epithelial barrier disruption and gut vascular barrier (GVB) damage in ethanol diet-fed mice. Co-housing vehicle-fed mice with HPP-fed mice alleviated ethanol-induced liver damage and endotoxemia. Moreover, fecal microbiota transplantation from HPP-fed mice into antibiotic-induced microbiota-depleted recipients also alleviated ethanol-induced liver injury and improved gut epithelial and vascular barrier. Our study demonstrated that HPP ameliorated ethanol-induced gut epithelial and vascular barrier dysfunction through alteration of gut microbiota, therefore preventing alcoholic liver damage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Bardoxolone methyl (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester, CDDO-Me) is a potent activator of nuclear factor erythroid 2-related factor 2 (Nrf2), which induces the expression of antioxidative-associated genes. CDDO-Me exerts protective effects against chronic inflammatory diseases in the kidneys and lungs. However, its pharmacological effects on metabolic dysfunction-associated steatohepatitis (MASH) caused by fat accumulation remain unknown. In this study, we examined the hepatoprotective effects of CDDO-Me in a diet-induced MASH mouse model and elucidated its pharmacological mechanisms using RNA-seq analysis., Experimental Approach: CDDO-Me was orally administered to mice fed a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD), and histological, biochemical, and transcriptomic analyses were performed on livers of mice that developed MASH., Key Results: CDDO-Me administration induced the expression of antioxidant genes and cholesterol transporters downstream of Nrf2 and significantly prevented the symptoms of MASH. Whole-transcriptome analysis revealed that CDDO-Me inhibited the inflammatory pathway that led to phagocyte recruitment, in addition to activating the Nrf2-dependent pathway. Among inflammatory pathways, CC chemokine ligands (CCL)3 and CCL4, which are downstream of NF-κB and are associated with the recruitment of macrophages expressing CC chemokine receptors (CCR)1 and CCR5, were released into the blood in MASH mice. However, CDDO-Me directly inhibited the expression of CCL3-CCR1 and CCL4-CCR5 in macrophages., Conclusions and Implications: Overall, we revealed the potent hepatoprotective effect of CDDO-Me in a MASH mouse model and demonstrated that its pharmacological effects were closely associated with a reduction of macrophage infiltration, through CCL3-CCR1 and CCL4-CCR5 inhibition, in addition to Nrf2-mediated hepatoprotective effects., (© 2024 British Pharmacological Society.)

Obesity is an unhealthy condition associated with various diseases characterized by excess fat accumulation. However, in China, the prevalence of obesity is 14.1%, and it remains challenging to achieve weight loss or resolve this issue through clinical interventions. Sanghuangpours vaninii (SPV) is a nutritional fungus with multiple pharmacological activities and serves as an ideal dietary intervention for combating obesity. In this study, a long-term high-fat diet (HFD) was administered to induce obesity in mice. Different doses of SPV and the positive drug simvastatin (SV) were administered to mice to explore their potential anti-obesity effects. SPV regulated weight, serum lipids, and adipocyte size while inhibiting inflammation and hepatic steatosis. Compared with the vehicle-treated HFD-fed mice, the lowest decreases in total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) were 9.72%, 9.29%, and 12.29%, respectively, and the lowest increase in high-density lipoprotein cholesterol (HDL-C) was 5.88% after treatment with different doses of SPV. With SPV treatment, the analysis of gut microbiota and serum lipids revealed a significant association between lipids and inflammation-related factors, specifically sphingomyelin. Moreover, Western blotting results showed that SPV regulated the toll-like receptor (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway in HFD-diet mice, which is related to inflammation and lipid metabolism. This research presents empirical proof of the impact of SPV therapy on obesity conditions.

Background: Obesity has been demonstrated as a risk factor that seriously affects health. Insoluble dietary fiber (IDF), as a major component of dietary fiber, has positive effects on obesity, inflammation and diabetes., Results: In this study, complex IDF was prepared using 50% enoki mushroom IDF, 40% carrot IDF, and 10% oat IDF. The effects and potential mechanism of complex IDF on obesity were investigated in C57BL/6 mice fed a high-fat diet. The results showed that feeding diets containing 5% complex IDF for 8 weeks significantly reduced mouse body weight, epididymal lipid index, and ectopic fat deposition, and improved mouse liver lipotoxicity (reduced serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase), fatty liver, and short-chain fatty acid composition. High-throughput sequencing of 16S rRNA and analysis of fecal metabolomics showed that the intervention with complex IDF reversed the high-fat-diet-induced dysbiosis of gut microbiota, which is associated with obesity and intestinal inflammation, and affected metabolic pathways, such as primary bile acid biosynthesis, related to fat digestion and absorption., Conclusion: Composite IDF intervention can effectively inhibit high-fat-diet-induced obesity and related symptoms and affect the gut microbiota and related metabolic pathways in obesity. Complex IDF has potential value in the prevention of obesity and metabolic syndrome. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize the delayed effects of radiation exposure and develop medical countermeasures. Radiation has been shown to damage adipose progenitor cells and increase liver fibrosis, such that it predisposes patients to developing metabolic-associated fatty liver disease (MAFLD) and insulin resistance. The risk of developing these conditions is compounded by the global rise of diets rich in carbohydrates and fats. Radiation persistently increases the signaling cascade of transforming growth factor β (TGFβ), leading to heightened fibrosis as characteristic of the delayed effects of radiation exposure. We investigate here a potential radiation medical countermeasure, IPW-5371, a small molecule inhibitor of TGFβRI kinase (ALK5). We found that mice exposed to sub-lethal whole-body irradiation and chronic Western diet consumption but treated with IPW-5371 had a similar body weight, food consumption, and fat mass compared to control mice exposed to radiation. The IPW-5371 treated mice maintained lower fibrosis and fat accumulation in the liver, were more responsive to insulin and had lower circulating triglycerides and better muscle endurance. Future studies are needed to verify the improvement by IPW-5371 on the structure and function of other metabolically active tissues such as adipose and skeletal muscle, but these data demonstrate that IPW-5371 protects liver and whole-body health in rodents exposed to radiation and a Western diet, and there may be promise in using IPW-5371 to prevent the development of MAFLD., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) has attracted increasing attention from the scientific community because of its severe but silent progression and the lack of specific treatment. Glucolipotoxicity triggers endoplasmic reticulum (ER) stress with decreased beta-oxidation and enhanced lipogenesis, promoting the onset of MASLD, whereas regular physical exercise can prevent MASLD by preserving ER and mitochondrial function. Thus, the hypothesis of this study was that high-intensity interval training (HIIT) could prevent the development of MASLD in high-fat (HF)-fed C57BL/6J mice by maintaining insulin sensitivity, preventing ER stress, and promoting beta-oxidation. Forty male C57BL/6J mice (3 months old) comprised 4 experimental groups: the control (C) diet group, the C diet + HIIT (C-HIIT) group, the HF diet group, and the HF diet + HIIT (HF-HIIT) group. HIIT sessions lasted 12 minutes and were performed 3 times weekly by trained mice. The diet and exercise protocols lasted for 10 weeks. The HIIT protocol prevented weight gain and maintained insulin sensitivity in the HF-HIIT group. A chronic HF diet increased ER stress-related gene and protein expression, but HIIT helped to maintain ER homeostasis, preserve mitochondrial ultrastructure, and maximize beta-oxidation. The increased sirtuin-1/peroxisome proliferator-activated receptor-gamma coactivator 1-alpha expression implies that HIIT enhanced mitochondrial biogenesis and yielded adequate mitochondrial dynamics. High hepatic fibronectin type III domain containing 5/irisin agreed with the antilipogenic and anti-inflammatory effects observed in the HF-HIIT group, reinforcing the antisteatotic effects of HIIT. Thus, we confirmed that practicing HIIT 3 times per week maintained insulin sensitivity, prevented ER stress, and enhanced hepatic beta-oxidation, impeding MASLD development in this mouse model even when consuming high energy intake from saturated fatty acids., Competing Interests: Author Declarations None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Aim: Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice., Method: C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated., Results: There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups., Conclusion: The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis., (© 2024 John Wiley & Sons Ltd.)

Menopause is characterized by a reduction in sex hormones in women and is associated with metabolic changes, including fatty liver and insulin resistance. Lifestyle changes, including a balanced diet and physical exercise, are necessary to prevent these undesirable changes. Strength training (ST) has been widely used because of the muscle and metabolic benefits it provides. Our study aims to evaluate the effects of ST on hepatic steatosis and insulin resistance in ovariectomized mice fed a high-fat diet (HFD) divided into four groups as follows: simulated sedentary surgery (SHAM-SED), trained simulated surgery (SHAM-EXE), sedentary ovariectomy (OVX-SED), and trained ovariectomy (OVX-EXE). They were fed an HFD for 9 weeks. ST was performed thrice a week. ST efficiently reduced body weight and fat percentage and increased lean mass in OVX mice. Furthermore, ST reduced the accumulation of ectopic hepatic lipids, increased AMPK phosphorylation, and inhibited the de novo lipogenesis pathway. OVX-EXE mice also showed a better glycemic profile, associated with greater insulin sensitivity identified by the euglycemic-hyperinsulinemic clamp, and reduced markers of hepatic oxidative stress compared with sedentary animals. Our data support the idea that ST can be indicated as a non-pharmacological treatment approach to mitigate metabolic changes resulting from menopause.

Introduction: Cigarettes containing nicotine (Nic) are a risk factor for the development of cardiovascular and metabolic diseases. We reported that Nic delivered via injections or e-cigarette vapor led to hepatic steatosis in mice fed with a high-fat diet. High-fructose corn syrup (HFCS) is the main sweetener in sugar-sweetened beverages (SSBs) in the US. Increased consumption of SSBs with HFCS is associated with increased risks of non-alcoholic fatty liver disease (NAFLD). Nicotinamide riboside (NR) increases mitochondrial nicotinamide adenine dinucleotide (NAD + ) and protects mice against hepatic steatosis. This study evaluated if Nic plus Coca-Cola ™ (Coke) with HFCS can cause hepatic steatosis and that can be protected by NR., Methods: C57BL/6J mice received twice daily intraperitoneal (IP) injections of Nic or saline and were given Coke (HFCS), or Coke with sugar, and NR supplementation for 10 weeks., Results: Our results show that Nic+Coke caused increased caloric intake and induced hepatic steatosis, and the addition of NR prevented these changes. Western blot analysis showed lipogenesis markers were activated (increased cleavage of the sterol regulatory element-binding protein 1 [SREBP1c] and reduction of phospho-Acetyl-CoA Carboxylase [p-ACC]) in the Nic+Coke compared to the Sal+Water group. The hepatic detrimental effects of Nic+Coke were mediated by decreased NAD + signaling, increased oxidative stress, and mitochondrial damage. NR reduced oxidative stress and prevented mitochondrial damage by restoring protein levels of Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1) signaling., Conclusion: We conclude that Nic+Coke has an additive effect on producing hepatic steatosis, and NR is protective. This study suggests concern for the development of NAFLD in subjects who consume nicotine and drink SSBs with HFCS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rivera, Espinoza-Derout, Hasan, Molina-Mancio, Martínez, Lao, Lee, Lee, Wilson, Sinha-Hikim and Friedman.)

The aim of this study was to investigate whether the therapeutic effect of theabrownin extracted from Qingzhuan tea (QTB) on metabolic dysfunction-associated steatosis liver disease (MASLD) is related to the regulation of intestinal microbiota and its metabolite short-chain fatty acids (SCFAs). Mice were divided into four groups and received normal diet (ND), high-fat diet (HFD) and HFD+QTB (180, 360 mg/kg) for 8 weeks. The results showed that QTB significantly reduced the body weight of HFD mice, ameliorated liver lipid and dyslipidemia, and increased the level of intestinal SCFAs in HFD mice. The results of 16 S rRNA showed that the relative abundance of Bacteroides, Blautia and Lachnoclostridium and their main metabolites acetate and propionate were significantly increased after QTB intervention. The relative abundance of Colidextribacter, Faecalibaculum and Lactobacillus was significantly reduced. QTB can also significantly up-regulate the expression of ATGL, PPARα, FFAR2 and FFAR3, and inhibit the expression of LXRα, SREBP-1c, FAS and HMGCR genes. This makes it possible to act as a prebiotic to prevent MASLD., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg -1 .day -1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Prenatal alcohol exposure (AE) affects cognitive development. However, it is unclear whether prenatal AE influences the metabolic health of offspring and whether postnatal AE exacerbates metabolic deterioration resulting from prenatal AE. Choline is a semi-essential nutrient that has been demonstrated to mitigate the cognitive impairment of prenatal AE. This study investigated how maternal choline supplementation (CS) may modify the metabolic health of offspring with prenatal and postnatal AE (AE/AE). C57BL/6J female mice were fed either a Lieber-DeCarli diet with 1.4% ethanol between embryonic day (E) 9.5 and E17.5 or a control diet. Choline was supplemented with 4 × concentrations versus the control throughout pregnancy. At postnatal week 7, offspring mice were exposed to 1.4% ethanol for females and 3.9% ethanol for males for 4 weeks. AE/AE increased hepatic triglyceride accumulation in male offspring only, which was normalized by prenatal CS. Prenatal CS also improved glucose tolerance compared to AE/AE animals. AE/AE suppressed hepatic gene expression of peroxisome proliferator activated receptor alpha ( Ppara ) and low-density lipoprotein receptor ( Ldlr ), which regulate fatty acid catabolism and cholesterol reuptake, respectively, in male offspring. However, these changes were not rectified by prenatal CS. In conclusion, AE/AE led to an increased risk of steatosis and was partially prevented by prenatal CS in male mice.

Background: Recent reports have unveiled the potential utility of l-carnitine to alleviate metabolic dysfunction-associated steatohepatitis (MASH) by enhancing mitochondrial metabolic function. However, its efficacy at preventing the development of HCC has not been assessed fully., Methods: l-carnitine (2 g/d) was administered to 11 patients with MASH for 10 weeks, and blood liver function tests were performed. Five patients received a serial liver biopsy, and liver histology and hepatic gene expression were evaluated using this tissue. An atherogenic plus high-fat diet MASH mouse model received long-term l-carnitine administration, and liver histology and liver tumor development were evaluated., Results: Ten-week l-carnitine administration significantly improved serum alanine transaminase and aspartate transaminase levels along with a histological improvement in the NAFLD activity score, while steatosis and fibrosis were not improved. Gene expression profiling revealed a significant improvement in the inflammation and profibrotic gene signature as well as the recovery of lipid metabolism. Long-term l-carnitine administration to atherogenic plus high-fat diet MASH mice substantially improved liver histology (inflammation, steatosis, and fibrosis) and significantly reduced the incidence of liver tumors. l-carnitine directly reduced the expression of the MASH-associated and stress-induced transcriptional factor early growth response 1. Early growth response 1 activated the promoter activity of neural precursor cell expressed, developmentally downregulated protein 9 (NEDD9), an oncogenic protein. Thus, l-carnitine reduced the activation of the NEDD9, focal adhesion kinase 1, and AKT oncogenic signaling pathway., Conclusions: Short-term l-carnitine administration ameliorated MASH through its anti-inflammatory effects. Long-term l-carnitine administration potentially improved the steatosis and fibrosis of MASH and may eventually reduce the risk of HCC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Kimchi is a traditional fermented food that contains abundant nutrients and functional ingredients with various health benefits. We previously reported that kimchi active components suppress hepatic steatosis caused by endoplasmic reticulum (ER) stress in vitro and in vivo. Therefore, we assessed the effect of kimchi on the inhibition of hepatic steatosis caused by ER stress in HepG2 cells and C57BL/6N mice to verify the hypothesis that kimchi may potentially inhibit nonalcoholic fatty liver disease. We investigated the effect of kimchi on cell viability and triglyceride concentrations in cells and on lipid profile, lipid accumulation, and expression of related genes in cells and mice with hepatic steatosis. A mechanistic study was also performed using the liver X receptor α agonist T0901317 and the AMP-activated protein kinase agonist AICAR. Kimchi was noncytotoxic and effectively reduced triglyceride concentrations and suppressed hepatic steatosis-related gene expression in cells and mice. Additionally, kimchi recovered weight loss, lowered the serum and liver tissue lipid profiles, suppressed lipid accumulation, and reduced the effects of T0901317 and AICAR on lipogenic gene expression in tunicamycin-treated mice. Our results highlight that kimchi could prevent hepatic steatosis caused by ER stress in cells and mice., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

(1) Background: Modulators of the Neuropeptide Y (NPY) system are involved in energy metabolism, but the effect of NPY receptor antagonists on metabolic-dysfunction-associated steatotic liver disease (MASLD), a common obesity-related comorbidity, are largely unknown. In this study, we report on the effects of antagonists of the NPY-2 receptor (Y2R) in comparison with empagliflozin and semaglutide, substances that are known to be beneficial in MASLD. (2) Methods: Diet-induced obese (DIO) male Wistar rats were randomized into the following treatment groups: empagliflozin, semaglutide ± PYY 3-36 , the Y2R antagonists JNJ 31020028 and a food-restricted group, as well as a control group. After a treatment period of 8 weeks, livers were weighed and histologically evaluated. QrtPCR was performed to investigate liver inflammation and de novo lipogenesis (in liver and adipose tissue). Serum samples were analysed for metabolic parameters. (3) Results: Semaglutide + PYY 3-36 led to significant weight loss, reduced liver steatosis ( p = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis ( p = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats ( p ≤ 0.0001). Food restriction also resulted in significantly reduced weight, steatosis, and hepatic de novo lipogenesis. (4) Conclusions: Body weight reduction (e.g., by food restriction or drugs like semaglutide ± PYY 3-36 ) is effective in improving liver steatosis in DIO rats. Remarkably, the body-weight-neutral Y2R antagonists may be effective in preventing liver steatosis through a reduction in de novo lipogenesis, making this drug class a candidate for the treatment of (early) MASLD.

Metabolic dysfunction-associated steatohepatitis (MASH) is always accompanied with hepatic fibrosis that could potentially progress to liver cirrhosis and hepatocellular carcinoma. Employing a rat model, we evaluated the role of human placental extract (HPE) to arrest the progression of hepatic fibrosis to cirrhosis in patients with MASH. SHRSP5/Dmcr rats were fed with a high-fat and high-cholesterol diet for 4 weeks and evaluated for the development of steatosis. The animals were divided into control and treated groups and received either saline or HPE (3.6 ml/kg body weight) subcutaneously thrice a week. A set of animals were killed at the end of 6th, 8th, and 12th weeks from the beginning of the experiment. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hepatic malondialdehyde (MDA), and glutathione content were measured. Immunohistochemical staining was performed for α-smooth muscle actin (α-SMA), 4-hydroxy-2-nonenal (4-HNE), collagen type I, and type III. Control rats depicted progression of liver fibrosis at 6 weeks, advanced fibrosis and bridging at 8 weeks, and cirrhosis at 12 weeks, which were significantly decreased in HPE-treated animals. Treatment with HPE maintained normal levels of MDA and glutathione in the liver. There was marked decrease in the staining intensity of α-SMA, 4-HNE, and collagen type I and type III in HPE treated rats compared with control animals. The results of the present study indicated that HPE treatment mediates immunotropic, anti-inflammatory, and antioxidant responses and attenuates hepatic fibrosis and early cirrhosis. HPE depicts therapeutic potential to arrest the progression of MASH towards cirrhosis., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Chaenomeles sinensis (Thouin) Koehne fruit is a rich source of medicinally and nutritionally important natural phytochemicals that benefit human health. Based on the information provided, we hypothesized that Chaenomeles sinensis (Thouin) Koehne fruit polyphenols (CSFP) possessed in vivo protective effect of on high-fat diet (HFD)-induced obesity and hepatic steatosis. Specific pathogen-free male C57BL/6J mice were randomly divided into 3 groups and fed with a low-fat diet, HFD, or HFD supplemented with CSFP by intragastric administration for 14 weeks. Obesity-related biochemical indexes and hepatic gene expression profile were determined. The findings of this study demonstrated notable reductions in body weight gain, serum triglycerides, total cholesterol, low-density lipoprotein cholesterol, and steatosis grade in the group supplemented with CSFP compared with the HFD group. Gene expression analysis provided insights into the molecular mechanisms, demonstrating that CSFP downregulated the expression of key genes involved in lipogenesis (e.g., Fas, Fads2, Scd1) and upregulated the genes associated with fatty acid oxidation (e.g., Pparα, Cpt1a, Acox1), while also suppressing genes implicated in cholesterol homeostasis (e.g., HMGCoR, Insig1, AdipoR2). These molecular changes suggest that CSFP exerts protective effects by modulating hepatic lipid metabolism pathways, thereby mitigating the metabolic derangements associated with HFD-induced obesity and hepatic steatosis., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this study, we evaluated the enrichment efficiency of lutein in eggs and its function in preventing fatty liver hemorrhagic syndrome (FLHS) in aged laying hens. Five groups of laying hens (65 wk old) were fed basal diets supplemented with 0, 30, 60, 90, or 120 mg/kg of lutein. The supplementation period lasted 12 wk followed by 2 wk of lutein depletion in feed. The results revealed that lutein efficiently enriched the egg yolks and improved their color with a significant increase in relative redness (P < 0.001). Lutein accumulation increased in the egg yolk until day 10, then depletion reached a minimum level after 14 d. Overall, zeaxanthin content in all the groups was similar throughout the experimental period. However, triglycerides and total cholesterol were significantly decreased in the liver (P < 0.05) but not significantly different in the serum (P > 0.05). In the serum, the lipid metabolism enzyme acetyl-CoA synthetase was significantly reduced (P < 0.05), whereas dipeptidyl-peptidase 4 was not significantly different (P > 0.05), and there was no statistical difference of either enzyme in the liver (P > 0.05). Regarding oxidation and inflammation-related indexes, malondialdehyde, tumor necrosis factors alpha, interleukin-6, and interleukin-1 beta were decreased, whereas superoxide dismutase and total antioxidant capacity increased in the liver (P < 0.001). The function of lutein for the same indexes in serum was limited. It was concluded that lutein efficiently enriched the egg yolk of old laying hens to improve their color and reached the highest level on day 10 without being subject to a significant conversion into zeaxanthin. At the same time, lutein prevented liver steatosis in aged laying hens by exerting strong antioxidant and anti-inflammatory functions, but also through the modulation of lipid metabolism, which may contribute to reducing the incidence of FLHS in poultry., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Berberine (BBR) is a natural alkaloid with multiple biotical effects that has potential as a treatment for fatty liver hemorrhagic syndrome (FLHS). However, the mechanism underlying the protective effect of BBR against FLHS remains unclear. The present study aimed to investigate the effect of BBR on FLHS induced by a high-energy, low-protein (HELP) diet and explore the involvement of the gut microbiota and bile acid metabolism in the protective effects. A total of 90 healthy 140-day-old Hy-line laying hens were randomly divided into three groups, including a control group (fed a basic diet), a HELP group (fed a HELP diet), and a HELP+BBR group (high-energy, high-protein diet supplemented with BBR instead of maize). Our results show that BBR supplementation alleviated liver injury and hepatic steatosis in laying hens. Moreover, BBR supplementation could significantly regulate the gut's microbial composition, increasing the abundance of Actinobacteria and Romboutsia. In addition, the BBR supplement altered the profile of bile acid. Furthermore, the gut microbiota participates in bile acid metabolism, especially taurochenodeoxycholic acid and α-muricholic acid. BBR supplementation could regulate the expression of genes and proteins related to glucose metabolism, lipid synthesis (FAS, SREBP-1c), and bile acid synthesis (FXR, CYP27a1). Collectively, our findings demonstrate that BBR might be a potential feed additive for preventing FLHS by regulating the gut microbiota and bile acid metabolism.

The health benefits of soy foods are attributed to the high-quality protein and the bioactive compounds such as isoflavones. We previously reported that feeding obese (fa/fa) Zucker rats soy protein concentrates (SPCs) with low isoflavone (LIF) and high isoflavone (HIF) for 9 weeks significantly reduced liver steatosis compared to a casein control (C) diet. The current study extended the dietary treatments to 18 weeks to investigate the long-term effect of LIF and HIF SPC diets. 6-week-old male lean (L, n  = 21) and obese (O, n  = 21) Zucker rats were fed a casein C diet, LIF and HIF SPC diets for 18 weeks and body weight (BW) was recorded twice weekly. Rats were killed after 18 weeks to measure liver steatosis and serum aspartate aminotransferase and alanine aminotransferase. Obese rats had significantly greater final BW, liver weight, liver weight as the percentage of BW, and steatosis score compared to lean rats in all three dietary groups. The obese high-isoflavones (OHIF) group had significantly higher BW compared to obese control (OC) group ( P  < .0001) and obese low-isoflavones (OLIF) group ( P  = .01). OC group had significantly greater liver weight, liver weight as the percentage of BW, and liver steatosis score compared to OLIF ( P  = .0077, P  < .0001 and P  < .0001, respectively) and OHIF ( P  = .0094, P  < .0001, and P  < .0001, respectively) groups. Taken together, long-term feeding of SPC diets protected against liver steatosis regardless of isoflavone levels.

The current experiment aimed to investigate the effect of dietary glycine (Gly) supplementation on productive performance, egg quality, stress response, and fatty liver incidence in laying hens raised under heat stress (HS) conditions. A total of two hundred eighty 24-wk-old Lohmann Brown-Lite laying hens were randomly allotted to 1 of 4 dietary treatments with 7 replicates. The negative control (NC) diet was prepared to meet or exceed the nutrient and energy requirement for Lohmann Brown laying hens, whereas the positive control (PC) diet was formulated to increase AME n by 100 kcal/kg compared with the NC diet. Two additional diets were prepared by supplementing 0.341% and 0.683% Gly to the NC diet. All hens were exposed to cyclic HS at 31.4 ± 1.17°C for 8 h/d and 26.7 ± 1.10°C for the remaining time for a 12-wk trial. Results indicated that increasing supplementation of Gly in diets tended (linear, P = 0.088) to decrease the FCR of laying hens. Increasing supplementation of Gly in diets increased (linear, P < 0.05) eggshell lightness and decreased (linear, P < 0.05) egg yolk color. Moreover, a tendency for a quadratic association (P < 0.10) of serum aspartate aminotransferase and alanine aminotransferase concentrations with increasing supplementation of Gly was observed. Increasing supplementation of Gly in diets decreased (linear, P < 0.05) blood heterophil:lymphocyte ratio of laying hens. Hens fed the NC diet showed higher fatty liver incidence (P < 0.05) than those fed the PC diet, but increasing supplementation of Gly decreased (linear, P < 0.05) fatty liver incidence of laying hens. In conclusion, increasing supplementation of Gly up to 0.683% in diets decreases FCR, stress response, and fatty liver incidence in laying hens raised under HS conditions., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver disorder affecting a significant part of the global population. This study aimed to investigate the potential therapeutic effects of α-lipoic acid (α-LA) on the inflammatory response during simple steatosis development and progression into steatohepatitis. The study used the MASLD model in male Wistar rats that were fed a standard diet or a high-fat diet (HFD) for 8 weeks. Throughout the entire experiment, half of the animals received α-LA supplementation. The hepatic activity of pro-inflammatory n-6 and anti-inflammatory n-3 polyunsaturated fatty acid (PUFA) pathways and the concentration of arachidonic acid (AA) in selected lipid fractions were determined by the gas-liquid chromatography (GLC). The hepatic expression of proteins from inflammatory pathway was measured by the Western blot technique. The level of eicosanoids, cytokines and chemokines was assessed by the ELISA or multiplex assay kits. The results showed that α-LA supplementation attenuated the activity of n-6 PUFA pathway in FFA and DAG and increased the activity of n-3 PUFA pathway in PL, TAG and DAG. In addition, the administration of α-LA decreased the concentration of AA in DAG and FFA, indicating its potential protective effect on the deterioration of simple hepatic steatosis. The supplementation of α-LA also increased the expression of COX-1 and COX-2 with the lack of significant changes in prostaglandins profile. We observed an increase in the expression of 12/15-LOX, which was reflected in an increase in lipoxin A4 (LXA4) level. A decrease in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines was also noticed in the liver of rats treated with HFD and α-LA. Our observations confirm that α-LA treatment has potential protective effects on inflammation development in the MASLD model. We believe that α-LA has a preventive impact when it comes to the progression of simple steatosis lesions to steatohepatitis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Maternal dietary patterns during pregnancy have been demonstrated to impact the structure of the gut microbiota in offspring, altering their susceptibility to diseases. This study is designed to elucidate whether the impact of folic acid supplementation during pregnancy on hepatic steatosis in male offspring of rat dams exposed to a high-fat diet (HFD) is related to gut-liver axis homeostasis. In this study, female rats were administered a HFD and simultaneously supplemented with 5 mg/kg folic acid throughout their pregnancy. Histopathological examination showed that folic acid supplementation effectively ameliorated hepatic lipid accumulation and inflammatory infiltrate in male offspring subjected to a maternal HFD. Maternal folic acid supplementation reduced the abundance of Desulfobacterota and the Firmicutes / Bacteroidota (F/B) ratio in male offspring. The expression of tight junction proteins in the colon was significantly upregulated, and the serum LPS level was significantly reduced. Furthermore, there was a notable reduction in the hepatic expression of the TLR4/NF-κB signaling pathway and subsequent inflammatory mediators. Spearman's correlation analysis revealed significant associations between hepatic inflammation-related indices and several gut microbiota, particularly Desulfobacterota and Lactobacillus . With a reduction in hepatic inflammation, the expression of PPAR-α was upregulated, and the expression of SREBP-1c and its downstream lipid metabolism-related genes was downregulated. In summary, folic acid supplementation during pregnancy modulates gut microbiota and enhances intestinal barrier integrity in male offspring of HFD dams. This helps reduce the LPS leakage and suppress the expression of TLR4/NF-κB pathway in the liver, thereby improving lipid metabolism disorders, and alleviating hepatic steatosis.

Accumulating evidence has shown that gut microbiota and its metabolites have important significance in the etiology of obesity and related disorders. Prebiotics prevent and alleviate obesity by modulating the gut microbiota. However, how pectin oligosaccharides (POS) derived from pectin degradation affect gut microbiota and obesity remains unclear. To investigate the potential anti-obesity effects of POS, mice were fed a high-fat diet (HFD) for 12 weeks and a POS supplement with drinking water during the last 8 weeks. The outcomes demonstrated that POS supplementation in HFD-fed mice decreased body weight ( P < 0.01), improved glucose tolerance ( P < 0.001), reduced fat accumulation ( P < 0.0001) and hepatic steatosis, protected intestinal barrier, and reduced pro-inflammatory cytokine levels. After fecal metagenomic sequencing, the POS corrected the gut microbiota dysbiosis caused by the HFD, as shown by the increased populations of Bifidobacterium , Lactobacillus taiwanensis , and Bifidobacterium animalis , and decreased populations of Alistipes and Erysipelatoclostridium , which were previously considered harmful bacteria. Notably, the changed gut microbiota was associated with the obesity prevention of POS. These findings demonstrate that POS regulates particular gut microbiota, which is essential owing to its ability to prevent disorders associated with obesity.

Background: Hyperlipidemia, hepatic steatosis, and hyperglycemia are common metabolic complications of obesity. The objective of the present study is to investigate the in vivo protective effect of Averrhoa carambola L. fruit polyphenols (ACFP) on hyperlipidemia, hepatic steatosis, and hyperglycemia in mice with high-fat diet (HFD)-induced obesity and elucidate the mechanisms of action underlying the beneficial effects of ACFP. Thirty-six specific pathogen-free male C57BL/6J mice (4 weeks old, weighing 17.1-19.9 g) were randomly divided into three groups and fed with a low-fat diet (LFD, 10% fat energy), HFD (45% fat energy), or HFD supplemented with ACFP by intragastric administration for 14 weeks. Obesity-related biochemical indexes and hepatic gene expression levels were determined. The statistical analyses were conducted using one-way analysis of variance (ANOVA) followed by Duncan's multiple range test., Results: The results showed that the body weight gain, serum triglycerides, total cholesterol, glucose, insulin resistance index, and steatosis grade in the ACFP group decreased by 29.57%, 26.25%, 27.4%, 19.6%, 40.32%, and 40%, respectively, compared to the HFD group. Gene expression analysis indicated that ACFP treatment improved the gene expression profiles involved in lipid and glucose metabolism compared to the HFD group., Conclusion: ACFP protected from HFD-induced obesity and obesity-associated hyperlipidemia, hepatic steatosis, and hyperglycemia by improving lipid and glucose metabolism in mice. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Niemann-pick C1-like 1 (NPC1L1) mediates cholesterol absorption and plays a key role in the pathogenesis of nonalcoholic simple fatty liver (NASFL). Our previous study showed that curcumin reduced NPC1L1 expression and cholesterol absorption in Caco-2 cells. This study aimed to investigate whether curcumin could inhibit intestinal and hepatic NPC1L1 expression through suppressing sterol regulatory element binding protein-2 (SREBP-2) / hepatocyte nuclear factor 1α (HNF1α) pathway, then exert anti-NASFL effects. Six-week hamsters were fed high-fat diet (HFD) with or without 0.1% curcumin for 12 weeks. Curcumin supplementation lowered blood total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol levels (20.2%, 48.7%, and 36.5%), and reduced liver TC and TG contents (26.1% and 26.5%). Oil Red O staining demonstrated that curcumin significantly alleviated HFD-induced liver fat accumulation and hepatic steatosis, which was accompanied by reduced intestinal and hepatic NPC1L1, SREBP-2 and HNF1α expression (P < .05) and increased fecal neutral sterol excretion (114.5%). Furthermore, curcumin decreased cholesterol absorption in Caco-2 cells and HepG2 cells (49.2 % and 52.7 %). The inhibitory effects of curcumin on NPC1L1 expression and cholesterol absorption could be prevented by blockade of the SREBP-2 and HNF1α pathway. These findings indicated that curcumin protected against HFD-induced NASFL by inhibiting intestinal and hepatic NPC1L1 expression via down-regulation of SREBP-2/HNF1α pathway, thus reducing intestinal cholesterol absorption and hepatic biliary cholesterol reabsorption, consequently alleviating liver cholesterol accumulation and steatosis. Our study provides evidence for curcumin as a potential nutritional therapy for NASFL by regulating NPC1L1 and enterohepatic circulation of cholesterol., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Olanzapine (OLA), a widely used second-generation antipsychotic (SGA), causes weight gain and metabolic alterations when administered orally to patients. Recently, we demonstrated that, contrarily to the oral treatment which induces weight gain, OLA administered via intraperitoneal (i.p.) in male mice resulted in body weight loss. This protection was due to an increase in energy expenditure (EE) through a mechanism involving the modulation of hypothalamic AMPK activation by higher OLA levels reaching this brain region compared to those of the oral treatment. Since clinical studies have shown hepatic steatosis upon chronic treatment with OLA, herein we further investigated the role of the hypothalamus-liver interactome upon OLA administration in wild-type (WT) and protein tyrosine phosphatase 1B knockout (PTP1B-KO) mice, a preclinical model protected against metabolic syndrome. WT and PTP1B-KO male mice were fed an OLA-supplemented diet or treated via i.p. Mechanistically, we found that OLA i.p. treatment induces mild oxidative stress and inflammation in the hypothalamus in a JNK1-independent and dependent manner, respectively, without features of cell dead. Hypothalamic JNK activation up-regulated lipogenic gene expression in the liver though the vagus nerve. This effect concurred with an unexpected metabolic rewiring in the liver in which ATP depletion resulted in increased AMPK/ACC phosphorylation. This starvation-like signature prevented steatosis. By contrast, intrahepatic lipid accumulation was observed in WT mice treated orally with OLA; this effect being absent in PTP1B-KO mice. We also demonstrated an additional benefit of PTP1B inhibition against hypothalamic JNK activation, oxidative stress and inflammation induced by chronic OLA i.p. treatment, thereby preventing hepatic lipogenesis. The protection conferred by PTP1B deficiency against hepatic steatosis in the oral OLA treatment or against oxidative stress and neuroinflammation in the i.p. treatment strongly suggests that targeting PTP1B might be also a therapeutic strategy to prevent metabolic comorbidities in patients under OLA treatment in a personalized manner., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Also, the authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Cancer alters the function of multiple organs beyond those targeted by metastasis 1,2 . Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)