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To establish a mouse model of weak depression, we raised 6-week-old C57BL/6N mice in single (SH) or group housing (GH) conditions for 2 weeks. The SH group showed less social interaction with stranger mice, learning disability in behavioral tests, and lower plasma corticosterone levels. The cecal microbiota of the SH group showed significant segregation from the GH group in the principal coordinate analysis (PCoA). Transcriptome analysis of the amygdala and liver detected multiple differentially expressed genes (DEGs). In the amygdala of SH mice, suppression of the cyclic adenine monophosphate (cAMP) signal was predicted and confirmed by the reduced immunoreactivity of phosphorylated cAMP-responsive element-binding protein. In the liver of SH mice, downregulation of beta-oxidation was predicted. Interestingly, the expression levels of over 100 DEGs showed a significant correlation with the occupancy of two bacterial genera, Lactobacillus (Lactobacillaceae) and Anaerostipes (Lachnospiraceae). These bacteria-correlated DEGs included JunB, the downstream component of cAMP signaling in the amygdala, and carnitine palmitoyltransferase 1A (Cpt1a), a key enzyme of beta-oxidation in the liver. This trans-omical analysis also suggested that nicotinamide adenine dinucleotide (NAD) synthesis in the liver may be linked to the occupancy of Lactobacillus through the regulation of nicotinamide phosphoribosyltransferase (NAMPT) and kynureninase (KYNU) genes. Our results suggested that SH condition along with the presence of correlated bacteria species causes weak depression phenotype in young mice and provides a suitable model to study food ingredient that is able to cure weak depression. [ABSTRACT FROM AUTHOR]

Inflammation and oxidative stress are well known to induce the biogenesis of lipid droplets (LDs) in various cell types, in which fatty acids are deposited as components of triglycerides (TGs) and/or cholesterol esters. This metabolic shift is critical for cell protection against the toxicity of excess lipids or their oxidative derivatives produced under various stressful exposures, including oxidative stress. The effect of bacterial lipopolysaccharide (LPS) on LD formation in CNS structures was mainly studied on microglial cells, whereas its effect on lipid metabolism in neurons, potentially associated with LD formation, has been studied neither on cell lines nor on primary neuronal cultures. This work was carried out on the PC12 neuronal cell line, which is widely used to explore the mechanisms of neuroinflammation and neurodegeneration, aiming to study the effects of LPS on LD formation, neutral lipid accumulation, and metabolism of major lipid classes, as well as to elucidate the mechanism mediating these effects. PC12 cell incubation with LPS for 24 h led to a significant accumulation of LDs and an increase in the TG level. Etomoxir, a carnitine palmitoyltransferase 1 (CPT1) inhibitor, also induced an increase in an absolute TG content. To elucidate the metabolic pathways of TG accumulation, PC12 cells were preincubated with [3H]-oleic acid and then examined for radioactive label incorporation into major lipid classes. LPS caused an increase the level of TG and free oleic acid radioactivity, accompanied by a significant inhibition of oleic acid oxidation and a decrease the radioactivity of phospholipids. PC12 cell incubation with LPS also caused a decrease in CPT1 expression. Our data indicate that in PC12 cells, LPS suppresses CPT1 expression and fatty acid oxidation, leading to sequestration of excess fatty acids into TG and the formation of LDs. Under conditions of the bacterial pathogen action, this mechanism seems to represent a cell survival strategy that protects from lipotoxicity. [ABSTRACT FROM AUTHOR]

The pathogenesis of liver fibrosis requires activation of hepatic stellate cells (HSCs); once activated, HSCs lose intracellular fatty acids but the role of fatty acid oxidation and carnitine palmitoyltransferase 1A (CPT1A) in this process remains largely unexplored. CPT1A was found in HSCs of patients with fibrosis. Pharmacological and genetic manipulation of CPT1A were performed in human HSC cell lines and primary HCSs. Finally, we induced fibrosis in mice lacking CPT1A specifically in HSCs. Herein, we show that CPT1A expression is elevated in HSCs of patients with non-alcoholic steatohepatitis, showing a positive correlation with the fibrosis score. This was corroborated in rodents with fibrosis, as well as in primary human HSCs and LX-2 cells activated by transforming growth factor β1 (TGFβ1) and fetal bovine serum (FBS). Furthermore, both pharmacological and genetic silencing of CPT1A prevent TGFβ1- and FBS-induced HSC activation by reducing mitochondrial activity. The overexpression of CPT1A, induced by saturated fatty acids and reactive oxygen species, triggers mitochondrial activity and the expression of fibrogenic markers. Finally, mice lacking CPT1A specifically in HSCs are protected against fibrosis induced by a choline-deficient high-fat diet, a methionine- and choline-deficient diet, or treatment with carbon tetrachloride. These results indicate that CPT1A plays a critical role in the activation of HSCs and is implicated in the development of liver fibrosis, making it a potentially actionable target for fibrosis treatment. We show that the enzyme carnitine palmitoyltransferase 1A (CPT1A) is elevated in hepatic stellate cells (HSCs) in patients with fibrosis and mouse models of fibrosis, and that CPT1A induces the activation of these cells. Inhibition of CPT1A ameliorates fibrosis by preventing the activation of HSCs. [Display omitted] • CPT1A is overexpressed in HSCs from patients with fibrosis and positively correlates with fibrosis and NAFLD activity score. • Fatty acid oxidation is increased in activated HSCs and CPT1A inhibition blunts HSC activation by reducing mitochondrial activity. • In experimental models, CPT1A-induced fibrogenesis is dependent on ATP availability. • The specific deletion of CPT1A in mouse HSCs protects against fibrosis. [ABSTRACT FROM AUTHOR]

Understanding gene variations in people living under extreme conditions has the potential of curing diseases caused by exposure to heat, cold, fatty diets, hypoxia, and pathogens. One candidate gene associated with heat resistance is ACE1 , encoding angiotensin-converting enzyme 1. Associations have also been made between cold resistance or fatty diets and polymorphisms of several genes, including ACTN3 , encoding alpha-actinin-3, and CPTIA , encoding carnitine palmitoyltransferase 1A. A prominent role in resistance to hypoxia has been recognized for polymorphisms of EPAS1 , encoding endothelial PAS domain protein 1, and EGLN1 , encoding Egl-9 family hypoxia inducible factor 1. Variants conferring human resistance to pathogens include HBB , encoding hemoglobin subunit beta, and ACE2 , encoding angiotensin-converting enzyme 2. Genetic knowledge concerning such diseases as malaria and conditions such as hypoxia should continue to promote advances in gene therapy. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the effect of dietary taurine on lipid metabolism and liver injury in mice fed a diet high in oxidized fish oil. The ICR mice (six weeks old) were randomly assigned to six groups and fed different diets for 10 weeks: control (CON), normal plus 15% fresh fish oil diet (FFO), normal plus 15% oxidized fish oil diet (OFO), or OFO plus 0.6% (TAU1), 0.9% (TAU2) or 1.2% (TAU3) taurine. Compared to the CON group, OFO mice showed increased liver index, aspartate aminotransferase (AST) and malondialdehyde (MDA) levels in serum (p < 0.05). In addition, OFO mice had increased cholesterol (CHOL)/high-density lipoprotein cholesterol (HDL-C) and decreased HDL-C/low-density lipoprotein cholesterol (LDL-C) and n-6/n-3 polyunsaturated fatty acid (PUFA) ratio in serum (p < 0.05) compared with CON mice. Notably, dietary taurine ameliorated the liver index and AST and MDA levels in serum and liver in a more dose-dependent manner than OFO mice. In addition, compared to OFO mice, decreased levels of CHOL and ratio of CHOL/HDL-C and n-6 PUFA/n-3 PUFA in serum were found in TAU3-fed mice. Supplementation with TAU2 and TAU3 increased the relative mRNA expression levels of peroxisome proliferator-activated receptor α, adipose triglyceride lipase, lipoprotein lipase, hormone-sensitive lipase and carnitine palmitoyl transferase 1 in liver compared with the OFO group (p < 0.05). Moreover, impaired autophagy flux was detected in mice fed with the OFO diet, and this was prevented by taurine. These findings suggested that dietary taurine might provide a potential therapeutic choice against oxidative stress and lipid metabolism disorder. [ABSTRACT FROM AUTHOR]

Purpose: Metabolic dysfunction-associated fatty liver disease (MAFLD) is fueled by escalations in both sedentary behavior and caloric intake and is noted in obese type 2 diabetic (T2DM) patients. This study aimed to examine the effects of exercise and the phytoestrogen genistein in mice fed a high fat (60% fat) high sugar (55% fructose with 45% sucrose), HFHS diet. Methods: Male C57BL/6J mice were assigned to five groups: HFHS, HFHS with genistein (600 mg/kg diet, HFHS+Gen), HFHS with moderate exercise (HFHS+Ex), and HFHS with combined genistein and moderate exercise (HFHS-Gen+Ex). Control lean mice were fed standard chow and water. Exercise consisted of 30-minute sessions of treadmill running five days/week for the 12-week study duration. Body weight was assessed weekly. Liver, kidney, fecal pellets and serum were extracted at the end of the study and maintained at − 80°C. Results: After 12 weeks of treatment, mice in the HFHS group had the highest hepatic lipid content. Plasma levels of glucose, insulin, leptin, cholesterol, amylin, and total fat content were significantly elevated in HFHS mice compared to control mice. HFHS feeding increased protein expression of carnitine palmitoyltransferase 1b (CPT-1b isoform) in gastrocnemius, CPT1a, glucose transporter protein 2 (GLUT2), glucocorticoid receptor (GR), and fructose 1,6-bisphosphate 1 (FBP1) expression in liver. Exercise alone had minor effects on these metabolic abnormalities. Genistein alone resulted in improvements in body weight, fat content, amylin, insulin sensitivity, and liver histopathology, GR, FBP1, and acetyl-CoA carboxylase 1 (ACC1). Combination treatment resulted in additional metabolic improvements, including reductions in hepatic lipid content and lipid area, alanine transferase activity, CPT1b, and CPT1a. Conclusion: Our results indicate that a HFHS diet is obesogenic, inducing metabolic perturbations consistent with T2DM and MAFLD. Genistein alone and genistein combined with moderate intensity exercise were effective in reducing MAFLD and the aberrations induced by chronic HFHS feeding. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), hepatic fibrosis and even hepatocellular carcinoma, is a liver disease worldwide without approved therapeutic drugs. Baicalein (BAL), a flavonoid compound extracted from the Traditional Chinese Medicine (TCM) Scutellariae Radix (Scutellaria baicalensis Georgi.), has been used in TCM clinical practice for thousands of years to treat liver diseases due to its "hepatoprotective effect". However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that oral administration of BAL significantly decreased excess serum levels of triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST) as well as hepatic TG in fructose-fed rats. Attenuation of the increased vacuolization and Oil Red O staining area was evident on hepatic histological examination in BAL-treated rats. Mechanistically, results of RNA-sequencing, western-blot, real-time quantitative PCR (RT-qPCR) and hepatic metabolomics analyses indicated that BAL decreased fructose-induced excessive nuclear expressions of mature sterol regulatory element-binding protein 1c (mSREBP1c) and carbohydrate response element-binding protein (ChREBP), which led to the decline of lipogenic molecules [including fatty acid synthase (FASN), stearoyl-CoA desaturase 1 (SCD1), elongation of very long chain fatty acids 6 (ELOVL6), acetyl-CoA carboxylase (ACC)], accompanying with the alternation of hepatic fatty acids composition. Meanwhile, BAL enhanced fatty acid oxidation by activating AMPK/PGC1α signaling axis and PPARα signal pathway, which elicited high expression of carnitine palmitoyl transferase 1α (CPT1α) and Acyl-CoA oxidase 1 (ACO1) in livers of fructose-fed rats, respectively. BAL ameliorated fructose-induced hepatic steatosis, which is associated with regulating fatty acid synthesis, elongation and oxidation. [ABSTRACT FROM AUTHOR]

This experiment simulated the hypoxic environment caused by actual production operations in fish farming (i.e., catching, gathering, transferring, and weighting) to study the effects of acute hypoxic conditions on the physiological and metabolic responses of triploid rainbow trout (O. mykiss). Two groups of fish weighting 590 g were sampled in the normoxia group (dissolved oxygen above 7 mg/L) and hypoxia group (dissolved oxygen ranged from 2 to 5 mg/L for 10 min). The results showed that 1) regarding stress response, hypoxia increased plasma levels of cortisol, heat shock protein 70 (HSP-70), lysozyme, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and creatine phosphokinase (CPK); induced the expression of hepatic genes encoding nuclear factor erythroid 2 related factor 2 (Nrf2), interferon γ (IFN-γ) and interleukin-1β (IL-1β). 2) Regarding metabolism response, hypoxia increased plasma levels of globulin (GLOB), glucose (GLU), triglyceride (TG) and lactate dehydrogenase (LDH); upregulated the hepatic gene expression of phosphoenolpyruvate carboxykinase, (PEPCK), pyruvate dehydrogenase kinase (PDK1), acetyl-CoA carboxylase (ACC) and acetyl-CoA oxidase (ACO); downregulated the hepatic gene expression of carnitine palmitoyl transferase 1 (CPT1); and unchanged the expression of hepatic genes in glycolysis and autophagy. 3) In response to hypoxia-inducible factors (HIFs), the hepatic HIF-2α gene was activated in the hypoxia group, but HIF-1α gene expression remained unchanged. Thus, during acute hypoxic stress, triploid rainbow trout were in a defensive state, with an enhanced immune response and altered antioxidant status. Additionally, the hepatic mitochondrial oxidation of glucose- and lipid-derived carbon in trout was suppressed, and hepatic gluconeogenesis and lipid synthesis were activated, which might be regulated by the HIF-2α pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: Heat stress (HS) represents an environmental and socio-economic burden to the poultry industry worldwide. However, the underpinning mechanisms for HS responses are still not well defined. Here, we used a high-throughput analysis to determine the metabolite profiles in acute and chronic heat-stressed broilers in comparison with thermoneutral and pair-fed birds. The results showed that HS altered several duodenal metabolites in a duration-dependent manner and identified potential metabolite signatures. Heat stress (HS) is devastating to poultry production sustainability worldwide. In addition to its adverse effects on growth, welfare, meat quality, and mortality, HS alters the gut integrity, leading to dysbiosis and leaky gut syndrome; however, the underlying mechanisms are not fully defined. Here, we used a high-throughput mass spectrometric metabolomics approach to probe the metabolite profile in the duodenum of modern broilers exposed to acute (AHS, 2 h) or chronic cyclic (CHS, 8 h/day for 2 weeks) HS in comparison with thermoneutral (TN) and pair-fed birds. Ultra high performance liquid chromatography coupled with high resolution mass spectrometry (UHPLC–HRMS) identified a total of 178 known metabolites. The trajectory analysis of the principal component analysis (PCA) score plots (both 2D and 3D maps) showed clear separation between TN and each treated group, indicating a unique duodenal metabolite profile in HS birds. Within the HS groups, partial least squares discriminant analysis (PLS-DA) displayed different clusters when comparing metabolite profiles from AHS and CHS birds, suggesting that the metabolite signatures were also dependent on HS duration. To gain biologically related molecule networks, the above identified duodenal metabolites were mapped into the Ingenuity Pathway Analysis (IPA) knowledge-base and analyzed to outline the most enriched biological functions. Several common and specific top canonical pathways were generated. Specifically, the adenosine nucleotide degradation and dopamine degradation pathways were specific for the AHS group; however, the UDP-D-xylose and UDP-D-glucuronate biosynthesis pathways were generated only for the CHS group. The top diseases enriched by the IPA core analysis for the DA metabolites, including cancer, organismal (GI) injury, hematological, cardiovascular, developmental, hereditary, and neurological disorders, were group-specific. The top altered molecular and cellular functions were amino acid metabolism, molecular transport, small molecule biochemistry, protein synthesis, cell death and survival, and DNA damage and repair. The IPA-causal network predicted that the upstream regulators (carnitine palmitoyltransferase 1B, CPT1B; histone deacetylase 11, HDAC11; carbonic anhydrase 9, CA9; interleukin 37, IL37; glycine N-methyl transferase, GNMT; GATA4) and the downstream mediators (mitogen-activated protein kinases, MAPKs; superoxide dismutase, SOD) were altered in the HS groups. Taken together, these data showed that, independently of feed intake depression, HS induced significant changes in the duodenal metabolite profile in a duration-dependent manner and identified a potential duodenal signature for HS. [ABSTRACT FROM AUTHOR]

Mitochondrial remodeling is dysregulated in metabolic diseases but the underlying mechanism is not fully understood. We report here that BDNF (brain derived neurotrophic factor) provokes mitochondrial fission and clearance in skeletal muscle via the PRKAA/AMPK-PINK1-PRKN/Parkin and PRKAA-DNM1L/DRP1-MFF pathways. Depleting Bdnf expression in myotubes reduced fatty acid-induced mitofission and mitophagy, which was associated with mitochondrial elongation and impaired lipid handling. Muscle-specific bdnf knockout (MBKO) mice displayed defective mitofission and mitophagy, and accumulation of dysfunctional mitochondria in the muscle when they were fed with a high-fat diet (HFD). These animals also have exacerbated body weight gain, increased intramyocellular lipid deposition, reduced energy expenditure, poor metabolic flexibility, and more insulin resistance. In contrast, consuming a BDNF mimetic (7,8-dihydroxyflavone) increased mitochondrial content, and enhanced mitofission and mitophagy in the skeletal muscles. Hence, BDNF is an essential myokine to maintain mitochondrial quality and function, and its repression in obesity might contribute to impaired metabolism. Abbreviation: 7,8-DHF: 7,8-dihydroxyflavone; ACACA/ACC: acetyl Coenzyme A carboxylase alpha; ACAD: acyl-Coenzyme A dehydrogenase family; ACADVL: acyl-Coenzyme A dehydrogenase, very long chain; ACOT: acyl-CoA thioesterase; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; BDNF: brain derived neurotrophic factor; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CCL2/MCP-1: chemokine (C-C motif) ligand 2; CCL5: chemokine (C-C motif) ligand 5; CNS: central nervous system; CPT1B: carnitine palmitoyltransferase 1b, muscle; Cpt2: carnitine palmitoyltransferase 2; CREB: cAMP responsive element binding protein; DNM1L/DRP1: dynamin 1-like; E2: estrogen; EHHADH: enoyl-CoenzymeA hydratase/3-hydroxyacyl CoenzymeA dehydrogenase; ESR1/ER-alpha: estrogen receptor 1 (alpha); FA: fatty acid; FAO: fatty acid oxidation; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FFA: free fatty acids; FGF21: fibroblast growth factor 21; FUNDC1: FUN14 domain containing 1; HADHA: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; HFD: high-fat diet; iWAT: inguinal white adipose tissues; MAP1LC3A/LC3A: microtubule-associated protein 1 light chain 3 alpha; MBKO; muscle-specific bdnf knockout; IL6/IL-6: interleukin 6; MCEE: methylmalonyl CoA epimerase; MFF: mitochondrial fission factor; NTRK2/TRKB: neurotrophic tyrosine kinase, receptor, type 2; OPTN: optineurin; PA: palmitic acid; PARL: presenilin associated, rhomboid-like; PDH: pyruvate dehydrogenase; PINK1: PTEN induced putative kinase 1; PPARGC1A/PGC-1α: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PRKAA/AMPK: protein kinase, AMP-activated, alpha 2 catalytic subunit; ROS: reactive oxygen species; TBK1: TANK-binding kinase 1; TG: triacylglycerides; TNF/TNFα: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like kinase 1 [ABSTRACT FROM AUTHOR]

Background: Abnormal intracellular glucose/fatty acid metabolism of T cells has tremendous effects on their immuno-modulatory function, which is related to the pathogenesis of autoimmune diseases. However, the association between the status of intracellular metabolism of T cells and type 1 diabetes is unclear. This study aimed to investigate the uptake of glucose and fatty acids in T cells and its relationship with disease progression in type 1 diabetes. Methods: A total of 86 individuals with type 1 diabetes were recruited to detect the uptake of glucose and fatty acids in T cells. 2-NBDG uptake and expression of glucose transporter 1 (GLUT1); or BODIPY uptake and expression of carnitine palmitoyltransferase 1A(CPT1A) were used to assess the status of glucose or fatty acid uptake in T cells. Patients with type 1 diabetes were followed up every 3-6 months for 36 months, the progression of beta-cell function was assessed using generalized estimating equations, and survival analysis was performed to determine the status of beta-cell function preservation (defined as 2-hour postprandial C-peptide >200 pmol/L). Results: Patients with type 1 diabetes demonstrated enhanced intracellular glucose uptake of T cells as indicated by higher 2NBDG uptake and GLUT1 expression, while no significant differences in fatty acid uptake were observed. The increased T cells glucose uptake is associated with lower C-peptide and higher hemoglobin A1c levels. Notably, patients with low T cell glucose uptake at onset maintained high levels of C-peptide within 36 months of the disease course [fasting C-petite and 2-hour postprandial C-peptide are 60.6 (95%CI: 21.1-99.8) pmol/L and 146.3 (95%CI: 14.1-278.5) pmol/L higher respectively], And they also have a higher proportion of beta-cell function preservation during this follow-up period (P <0.001). Conclusions: Intracellular glucose uptake of T cells is abnormally enhanced in type 1 diabetes and is associated with beta-cell function and its progression. [ABSTRACT FROM AUTHOR]

To establish a mouse model of weak depression, we raised 6-week-old C57BL/6N mice in single (SH) or group housing (GH) conditions for 2 weeks. The SH group showed less social interaction with stranger mice, learning disability in behavioral tests, and lower plasma corticosterone levels. The cecal microbiota of the SH group showed significant segregation from the GH group in the principal coordinate analysis (PCoA). Transcriptome analysis of the amygdala and liver detected multiple differentially expressed genes (DEGs). In the amygdala of SH mice, suppression of the cyclic adenine monophosphate (cAMP) signal was predicted and confirmed by the reduced immunoreactivity of phosphorylated cAMP-responsive element-binding protein. In the liver of SH mice, downregulation of beta-oxidation was predicted. Interestingly, the expression levels of over 100 DEGs showed a significant correlation with the occupancy of two bacterial genera, Lactobacillus (Lactobacillaceae) and Anaerostipes (Lachnospiraceae). These bacteria-correlated DEGs included JunB, the downstream component of cAMP signaling in the amygdala, and carnitine palmitoyltransferase 1A (Cpt1a), a key enzyme of beta-oxidation in the liver. This trans-omical analysis also suggested that nicotinamide adenine dinucleotide (NAD) synthesis in the liver may be linked to the occupancy of Lactobacillus through the regulation of nicotinamide phosphoribosyltransferase (NAMPT) and kynureninase (KYNU) genes. Our results suggested that SH condition along with the presence of correlated bacteria species causes weak depression phenotype in young mice and provides a suitable model to study food ingredient that is able to cure weak depression. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a dramatic neurodegenerative disorder caused by the abnormal expansion of a CAG triplet in the huntingtin gene, producing an abnormal protein. As it leads to the death of neurons in the cerebral cortex, the patients primarily present with neurological symptoms, but recently metabolic changes resulting from mitochondrial dysfunction have been identified as novel pathological features. The carnitine shuttle is a complex consisting of three enzymes whose function is to transport the long-chain fatty acids into the mitochondria. Here, its pharmacological modification was used to test the hypothesis that shifting metabolism to lipid oxidation exacerbates the HD symptoms. Behavioural and transcriptional analyses were carried out on HD Drosophila model, to evaluate the involvement of the carnitine cycle in this pathogenesis. Pharmacological inhibition of CPT1, the rate-limiting enzyme of the carnitine cycle, ameliorates the HD symptoms in Drosophila, likely acting on the expression of carnitine-related genes. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease (ALD) is a worldwide healthcare problem featured by inflammation, reactive oxygen species (ROS), and lipid dysregulation. Roxadustat is used for chronic kidney disease anemia treatment. As a specific inhibitor of prolyl hydroxylase, it can maintain high levels of hypoxia-inducible factor 1α (HIF-1α), through which it can further influence many important pathways, including the three featured in ALD. However, its effects on ALD remain to be elucidated. In this study, we used chronic and acute ALD mouse models to investigate the protective effects of roxadustat in vivo. Our results showed that long- and short-term alcohol exposure caused rising activities of serum transaminases, liver lipid accumulation, and morphology changes, which were reversed by roxadustat. Roxadustat-reduced fatty liver was mainly contributed by the reducing sterol-responsive element-binding protein 1c (SREBP1c) pathway, and enhancing β-oxidation through inducing peroxisome proliferator-activated receptor α (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) expression. Long-term alcohol treatment induced the infiltration of monocytes/macrophages to hepatocytes, as well as inflammatory cytokine expression, which were also blocked by roxadustat. Moreover, roxadustat attenuated alcohol caused ROS generation in the liver of those two mouse models mainly by reducing cytochrome P450 2E1 (CYP2E1) and enhancing superoxidase dismutase 1 (SOD1) expression. In vitro , we found roxadustat reduced inflammation and lipid accumulation mainly via HIF-1α regulation. Taken together, our study demonstrates that activation of HIF-1α can ameliorate ALD, which is contributed by reduced hepatic lipid synthesis, inflammation, and oxidative stress. This study suggested that roxadustat could be a potential drug for ALD treatment. [ABSTRACT FROM AUTHOR]

Chitosan oligosaccharides (COSs), oligomers of decomposed chitosan possess many biological functions including immunomodulatory, antitumor, and antiinflammation. The aim of this study was to investigate the protective effects of COS against free fatty acid (FFA)‐induced cellular hepatic steatosis and underlying mechanisms in HepG2 cells. Results showed that COS significantly reduced the lipid contents and elevated the activities of antioxidant enzymes including total‐superoxide dismutase, glutathione peroxidase, and catalase in FFA‐stimulated HepG2 cells. COS phosphorylated the acetyl‐CoA carboxylase and reduced both mRNA and protein levels of lipogenesis markers including fatty acid synthase and sterol regulatory element‐binding protein 1c. COS also significantly increased the expression levels of fatty acid oxidation‐related factors including carnitine palmitoyltransferase 1A, acyl‐coenzyme A oxidase 1, and peroxisome proliferators‐activated receptor α. Besides, COS markedly phosphorylated AMP‐activated protein kinase (AMPK). The inhibition of lipogenesis and the enhancement of fatty acid oxidation induced by COS were all blocked by AMPK antagonist (compound C), showing that the attenuation of hepatic steatosis by COS was dependent on AMPK activation. In conclusion, COS attenuated hepatic steatosis via suppressing lipid synthesis and enhancing fatty acid oxidation. AMPK was also involved in the alleviation of hepatic steatosis by COS. These results indicated that COS might be used as a potential ingredient to ameliorate nonalcoholic fatty liver disease. Practical applications: Nonalcoholic fatty liver disease (NAFLD) has been regarded as pathological fat deposition in the liver, which includes a range of pathologies, from steatosis to steatohepatitis, fibrosis, and cellular carcinoma. Our findings demonstrated that Chitosan oligosaccharides (COS) attenuated steatosis via improving lipid metabolism. COS suppressed lipogenesis and also enhanced fatty acid oxidation. Besides, the underlying molecular mechanism whereby COS elicited these beneficial effects has also been proved to be through the modulation of upstream protein kinase, AMP‐activated protein kinase. This study provides new knowledge to support that COS might be used as a food supplement for the prevention of NAFLD. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is a widespread disease, but no recognized drug treatment exists. Previous studies have shown that artemether (Art) can ameliorate carbon tetrachloride (CCl4)–induced liver fibrosis in mice. This study sets out to observe the therapeutic impact of Art on non-alcoholic steatohepatitis (NASH). Methods: Model mice were provided with a methionine- and choline-deficient (MCD) diet for 4 weeks or a high-fat diet (HFD) for 28 weeks, respectively, and then treated with Art. RNA sequencing (RNA-Seq) analyzed gene expression changes caused by Art treatment. The molecular mechanism of the therapeutic effects of Art on NASH was studied in the mouse liver and HepG2 cells. Results: Art treatment significantly attenuated hepatic lipid accumulation and liver damage in MCD diet– or HFD-induced NASH mice. The RNA-Seq analysis revealed lipid metabolism as a major pathway suppressed by Art administration, in addition to the regulation of inflammation pathways. Mechanistically, Art reduced lipid accumulation by repressing de novo lipogenesis of sterol regulatory element-binding protein-1c (SREBP-1c), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD1), promoting lipolysis of peroxisome proliferator–activated receptor-γ co-activator-1α (PGC1α), adipose triglyceride lipase (ATGL), and carnitine palmitoyltransferase I (CPT-1a) in NASH mouse liver and HepG2 cells. In addition, Art inhibited the secretion of pro-inflammatory factors and reduced inflammatory infiltration by effectively inhibiting M1 macrophage activation. Furthermore, Art inhibited transforming growth factor-beta 1 (TGF-β), and the SMAD signaling pathway mediates the development of liver fibrosis. Inclusion : Art improved fat deposition by repressing de novo lipogenesis and promoting lipolysis in vivo and in vitro. Furthermore, Art improved inflammation and fibrosis with a significant effect. It is a prospective therapeutic agent for NASH. [ABSTRACT FROM AUTHOR]

The current study was designed to evaluate the therapeutic efficacy of Zingiberene (ZB) against high-fat-diet (HFD)–induced obesity and its associated non-alcoholic fatty liver disease (NAFLD). NAFLD model was developed in rats by supplementation of HFD (20 g daily) initially for 15 weeks and 16th week onwards treated with ZB (50 mg/kg BW) for the period of 45 days. We evaluated the effects of ZB on glucose homeostasis, lipid profiles in both blood and tissue, and lipogenesis along with oxidative stress markers in liver. HFD supplementation significantly caused hyperglycemia, and hyperinsulinemia and insulin resistance thereby altered both circulatory and tissue lipids. At the same time, lipogenesis and oxidative stress in liver was noted in obese rats. On the other hand, supplementation of ZB (50 mg/kg BW) to obese rats successfully attenuated hyperglycemia, hyperinsulinemia, and hyperlipidemia in both blood and liver. ZB also regulated the activities of lipid metabolic marker enzymes (carnitine palmitoyl transferase, acetyl-CoA carboxylase, fatty acid synthase, and HMG CoA reductase) and suppressed oxidative stress via enhancement of activities of SOD, catalase, and GPx along with GSH content elevation in the liver. In conclusion, this study suggests that ZB supplementation might ameliorate the obesity-associated NAFLD via attenuation of elevated lipogenesis and oxidative stress in liver. [ABSTRACT FROM AUTHOR]

Angiopoietin‐like protein (ANGPTL) 4 is a key factor in the regulation of lipid and glucose metabolism in metabolic diseases. ANGPTL4 is highly expressed in various cancers, but the regulation of energy metabolism in tumours remains to be determined. This study explored the role of ANGPTL4 in aerobic glycolysis, glutamine consumption and fatty acid oxidation in nonsmall cell lung cancer (NSCLC) cells. Two NSCLC cell lines (A549 and H1299) were used to investigate the role of ANGPTL4 in energy metabolism by tracer techniques and with Seahorse XF technology in ANGPTLs4 knockdown cells. RNA microarrays and specific inhibitors were used to identify targets in ANGPTLs4‐overexpressing cells. The results showed that knockdown of ANGPTLs4 could inhibit energy metabolism and proliferation in NSCLC. ANGPTLs4 had no significant effect on glycolysis but affected glutamine consumption and fatty acid oxidation. Knockdown of ANGPTLs4 also significantly inhibited tumour metastasis and energy metabolism in mice and had a weak effect on glycolysis. RNA microarray analysis showed that ANGPTLs4 significantly affected glutaminase (GLS) and carnitine palmitoyl transferase 1 (CPT1). ANGPTLs4‐overexpressing cells were exposed to a glutamine deprivation environment, and cell proliferation and energy metabolism were significantly decreased but still differed from normal NSCLC cells. Treatment of ANGPTLs4‐overexpressing cells with GLS and CPT1 inhibitors simultaneously prevented the regulatory effects on cell proliferation and energy metabolism. ANGPTLs4 could promote glutamine consumption and fatty acid oxidation but not glycolysis or accelerate energy metabolism in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Disorders of mitochondrial carnitine–acylcarnitine cycle is a heterogeneous group of hereditary diseases of mitochondrial β-oxidation of fatty acids tested in NBS program in Zhejiang province, China. Large-scale studies reporting disorders of mitochondrial carnitine–acylcarnitine cycle among Chinese population in NBS are limited. The aim of this study was to explain the incidence and biochemical, clinical, and genetic characteristics of disorders of mitochondrial carnitine–acylcarnitine cycle in NBS. Methods: From January 2009 to June 2021, 4,070,375 newborns were screened by tandem mass spectrometry. Newborns with elevated C0 levels and/or C0/(C16 + C18) ratios were identified as having CPT1D, whereas those with decreased C0 levels and/or C0/(C16 + C18) ratios and/or elevated C12-C18:1 level were identified as having CPT2D or CACTD. Suspected positive patients were further subjected to genetic analysis. All confirmed patients received biochemical and nutritional treatment, as well as follow-up sessions. Results: Overall, 20 patients (12 with CPT1D, 4 with CPT2D, and 4 with CACTD) with disorders of mitochondrial carnitine–acylcarnitine cycle were diagnosed by NBS. The overall incidence of these disorders was one in 203,518 newborns. In toal, 11 patients with CPT1D exhibited increased C0 levels and C0/(C16 + C18) ratios. In all patients of CPT2D, all long chain acyl-carnitines levels were elevated except for case 14 having normal C12 levels. In all patients with CACTD, all long chain acyl-carnitines levels were elevated except for case 17 having normal C12, C18, and C18:1 levels. Most patients with CPT1D were asymptomatic. Overall, two of 4 patients with CPT2D did not present any clinical symptom, but other two patients died. In 4 cases with CACTD, the disease was onset after birth, and 75% patients died. In total, 14 distinct mutations were identified in CPT1A gene, of which 11 were novel and c.1910C > A (p.S637T), c.740C > T (p.P247L), and c.1328T > C (p.L443P) were the most common mutations. Overall, 3 novel mutations were identified in CPT2 gene, and the most frequent mutation was c.1711C > A (p.P571T). The most common variant in SLC25A20 gene was c.199-10T > G. Conclusion: Disorders of mitochondrial carnitine–acylcarnitine cycle can be detected by NBS, and the combined incidence of these disorders in newborns was rare in Zhejiang province, China. Most patients presented typical acylcarnitine profiles. Most patients with CPT1D presented normal growth and development, whereas those with CPT2D/CACTD exhibited a high mortality rate. Several novel CPT1A and CPT2 variants were identified, which expanded the variant spectrum. [ABSTRACT FROM AUTHOR]

Acetyl-CoA carboxylases (ACCs) are enzymes that catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. In mammals, ACC1 and ACC2 are two members of ACCs. ACC1 localizes in the cytosol and acts as the first and rate-limiting enzyme in the de novo fatty acid synthesis pathway. ACC2 localizes on the outer membrane of mitochondria and produces malonyl-CoA to regulate the activity of carnitine palmitoyltransferase 1 (CPT1) that involves in the β-oxidation of fatty acid. Fatty acid synthesis is central in a myriad of physiological and pathological conditions. ACC1 is the major member of ACCs in mammalian, mountains of documents record the roles of ACC1 in various diseases, such as cancer, diabetes, obesity. Besides, acetyl-CoA and malonyl-CoA are cofactors in protein acetylation and malonylation, respectively, so that the manipulation of acetyl-CoA and malonyl-CoA by ACC1 can also markedly influence the profile of protein post-translational modifications, resulting in alternated biological processes in mammalian cells. In the review, we summarize our understandings of ACCs, including their structural features, regulatory mechanisms, and roles in diseases. ACC1 has emerged as a promising target for diseases treatment, so that the specific inhibitors of ACC1 for diseases treatment are also discussed. [ABSTRACT FROM AUTHOR]

The overproduction of osteoclasts, leading to bone destruction in patients with rheumatoid arthritis (RA), is well established. However, little is known about the metabolic dysfunction of osteoclast precursors (OCPs) in RA. Herein, we show that increasing fatty acid oxidation (FAO) induces OCP fusion. Carnitine palmitoyltransferase IA (CPT1A), which is important for carnitine transportation and is involved in FAO in the mitochondria, is upregulated in RA patients. This metabolic change further increases the expression of clathrin heavy chain (CLTC) and clathrin light chain A (CLTA) by enhancing the binding of the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) to the promoters of CLTA and CLTC. This drives clathrin-dependent endocytosis pathway, which attenuates fusion receptors in the cellular membrane and contributes to increased podosome structure formation. This study reveals a new mechanism through which FAO metabolism participates in joint destruction in RA and provides a novel therapeutic direction for the development of drugs against bone destruction in patients with RA. [ABSTRACT FROM AUTHOR]

The present study aimed to figure out whether high‐fat diet could change the contents of SCFAs in the intestine and the effects of such changes on fatty liver diseases in Megalobrama amblycephala. The results showed that acetate concentration in the intestinal tissue and chyme of M. amblycephala was decreased when fish fed high‐fat diet (10% dietary fat) than that fed normal diet (5% dietary fat). Then, effects of sodium acetate (SA) on lipid metabolism, antioxidant capability and apoptosis of M. amblycephala hepatocytes treated by sodium palmitate (SP) were elucidated. It was showed that SP significantly increased cell damages, lipid accumulation, oxidative stress and apoptosis (p < 0.05). SA could reduce cell damages by decreasing the aspartate aminotransferase (AST) activity (p < 0.05), attenuate oxidative stress through reducing intracellular oxygen species (ROS) and malondialdehyde (MDA) contents (p < 0.05), alleviate lipid accumulation by decreasing total cholesterol (TC) and non‐esterified fatty acids (NEFA) contents (p < 0.05), along with down‐regulating acetyl CoA carboxylase (ACC) activity and up‐regulating carnitine palmitoyltransferase 1 (CPT‐1) mRNA expression (p < 0.05). In addition, SA increased mitochondrial membrane potential and reduced cell apoptosis caused by SP treatment. Transmission electron microscopy found that the structures of karyotheca, endoplasmic reticulum and mitochondria in hepatocytes were badly damaged by SP and then repaired by SA. Our findings may provide new ideas and basis for high‐fat diet and SCFAs (acetate) used in aquaculture practice. [ABSTRACT FROM AUTHOR]

Kidney cancer is one of the top ten cancer diagnosed worldwide and its incidence has increased the last 20 years. Clear Cell Renal Cell Carcinoma (ccRCC) are characterized by mutations that inactivate the von Hippel-Lindau (VHL) tumor suppressor gene and evidence indicated alterations in metabolic pathways, particularly in glutamine metabolism. We previously identified a small molecule, STF-62247, which target VHL-deficient renal tumors by affecting late-stages of autophagy and lysosomal signaling. In this study, we investigated ccRCC metabolism in VHL-deficient and proficient cells exposed to the small molecule. Metabolomics profiling using 1H NMR demonstrated that STF-62247 increases levels of glucose, pyruvate, glycerol 3-phosphate while glutamate, asparagine, and glutathione significantly decreased. Diminution of glutamate and glutamine was further investigated using mass spectrometry, western blot analyses, enzymatic activities, and viability assays. We found that expression of SLC1A5 increases in VHL-deficient cells treated with STF-62247, possibly to stimulate glutamine uptake intracellularly to counteract the diminution of this amino acid. However, exogenous addition of glutamine was not able to rescue cell viability induced by the small molecule. Instead, our results showed that VHL-deficient cells utilize glutamine to produce fatty acid in response to STF-62247. Surprisingly, this occurs through oxidative phosphorylation in STF-treated cells while control cells use reductive carboxylation to sustain lipogenesis. We also demonstrated that STF-62247 stimulated expression of stearoyl-CoA desaturase (SCD1) and peripilin2 (PLIN2) to generate accumulation of lipid droplets in VHL-deficient cells. Moreover, the carnitine palmitoyltransferase 1A (CPT1A), which control the entry of fatty acid into mitochondria for β-oxidation, also increased in response to STF-62247. CPT1A overexpression in ccRCC is known to limit tumor growth. Together, our results demonstrated that STF-62247 modulates cellular metabolism of glutamine, an amino acid involved in the autophagy-lysosome process, to support lipogenesis, which could be implicated in the signaling driving to cell death. [ABSTRACT FROM AUTHOR]

Gliomas are intricate tumors with numerous metabolic and genetic abnormalities contributing to their aggressive phenotypes and poor prognoses. The study aims at identifying the key molecular metabolic as well as gene expressional variations that could be used to differentiate between different grades of glioma to obtain deeper insights the about metabolic status of glioma that may serve as good candidates of diagnosis in future. In the present study, the metabolomic profiling along with clinical and expressional analyses of glioma biopsies (n = 52; patients comprising both of benign and malignant lesions) was analyzed. The biopsies were subjected to gene/protein expressional analysis using RT-PCR and western blotting and also were subjected to metabolite analyses. The results of the gene/protein expressional analysis exhibited elevated levels of carnitine palmitoyltransferase, monoglyceride lipase, human phosphofructokinase, and isocitrate dehydrogenase in higher grades of glioma when compared to those of control. Our study suggested that the metabolites and gene/protein expressional levels were found to be discriminative among the grades of glioma. The study is deemed as a provider of deeper insights that are essential for differential therapeutic approaches that specifically target the dysregulated metabolome to the benefit of patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Altered lipid metabolism is closely related to the occurrence and development of hepatocellular carcinoma (HCC). Carnitine palmitoyltransferase 1C (CPT1C) is a member of CPT1 family and plays a key role in cancer development and progression. However, how microRNAs (miRNAs) regulate CPT1C-mediated fatty acid transport and oxidation remains to be elucidated. Methods: Oil Red O staining, mitochondrial, and lipid droplets immunofluorescence staining were used to detect the functions of miR-377-3p and CPT1C in fatty acid oxidation. Colocalization of palmitate and mitochondria was performed to investigate the function of miR-377-3p and CPT1C in fatty acid transport into mitochondria. Fatty acid oxidation (FAO) assay was used to detect the function of miR-377-3p and CPT1C in FAO. Cell proliferation, migration and invasion assays and animal experiments were used to evaluate the role of miR-377-3p/CPT1C axis in HCC progression in vitro and in vivo. Immunofluorescence staining was used to identify the clinical significance of miR-377-3p and CPT1C in HCC patients. Results: MiR-377-3p inhibits CPT1C expression by targeting its 3'-untranslated region. Through repression of CPT1C, miR-377-3p suppresses fatty acid oxidation by preventing fatty acid from entering into mitochondria and decreasing ATP production in HCC cells. Inhibiting fatty acid oxidation abolishes the ability of miR-377-3p/CPT1C axis to regulate HCC proliferation, migration, invasion and metastasis in vitro and in vivo. In HCC patients, CPT1C is significantly upregulated, and miR-377-3p expression and lipid droplets are negatively correlated with CPT1C expression. High expression of miR-377-3p and CPT1C predict better and worse clinical outcomes, respectively. Conclusions: We uncover the key function and the relevant mechanisms of the miR-377-3p/CPT1C axis in HCC, which might provide a potential target for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Decidualization accompanies with extensive stromal cell proliferation and differentiation, is a crucial step in early pregnancy. Aberrant decidualization is linked to infertility and miscarriage but the mechanisms remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is an enzyme catalyzing key steps in the fatty acid beta-oxidation pathway. The objective of this study was to investigate the role of CPT1A in decidualization during early pregnancy. An increased expression of CPT1A was found both in Days 6 and 7 as compared with in Days 1, 4 and 5. Further examination showed that on days 5–7 of pregnancy, the protein level of CPT1A was strongly up-regulated at implantation sites compared with inter-implantation sites, the location of CPT1A protein was distributed in the decidual zone. Upon further exploration, CPT1A expression was significantly increased in response to artificially induced decidualization both in vivo and in vitro. After down-regulating CPT1A expression by CPT1A-small interfering RNA (siCPT1A) in primary mouse endometrial stromal cells, expressions of decidualization markers and cell proliferation markers were decreased. After siCPT1A was transfected into the mouse uterus, decidualization impaired and then led to the loss of the implanted embryos. Thus, CPT1A is important for decidualization in mice and it may regulate the stromal cell proliferation progress. It is worth noting that the expression of CPT1A protein of human decidua was significantly decreased in spontaneous abortion groups compared to normal pregnancy groups. Collectively, CPT1A is essential for endometrium of early pregnant mice and humans. • The aim of this study was to determine the expression pattern of CPT1A gene in mouse uterus during the early pregnancy. • Our study provided an evidence that highly expressed CPT1A is important for cell proliferation during mouse decidualization. • The protein level of CPT1A in the decidua of spontaneous abortion group was significantly lower than that in the decidua of normal pregnancy group. [ABSTRACT FROM AUTHOR]

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation. Oxylipins are lipid mediators generated during infection for regulating inflammatory responses, but how they are removed is not completely clear. Here the authors show that cellular oxylipin removal is linked to mitochondria β-oxidation by CPT1, a mitochondria lipid importer protein, to serve as a metabolic checkpoint for oxylipin homeostasis and inflammation. [ABSTRACT FROM AUTHOR]

Autophagy-related gene 3 (ATG3) is an enzyme mainly known for its actions in the LC3 lipidation process, which is essential for autophagy. Whether ATG3 plays a role in lipid metabolism or contributes to non-alcoholic fatty liver disease (NAFLD) remains unknown. By performing proteomic analysis on livers from mice with genetic manipulation of hepatic p63, a regulator of fatty acid metabolism, we identified ATG3 as a new target downstream of p63. ATG3 was evaluated in liver samples from patients with NAFLD. Further, genetic manipulation of ATG3 was performed in human hepatocyte cell lines, primary hepatocytes and in the livers of mice. ATG3 expression is induced in the liver of animal models and patients with NAFLD (both steatosis and non-alcoholic steatohepatitis) compared with those without liver disease. Moreover, genetic knockdown of ATG3 in mice and human hepatocytes ameliorates p63- and diet-induced steatosis, while its overexpression increases the lipid load in hepatocytes. The inhibition of hepatic ATG3 improves fatty acid metabolism by reducing c-Jun N-terminal protein kinase 1 (JNK1), which increases sirtuin 1 (SIRT1), carnitine palmitoyltransferase 1a (CPT1a), and mitochondrial function. Hepatic knockdown of SIRT1 and CPT1a blunts the effects of ATG3 on mitochondrial activity. Unexpectedly, these effects are independent of an autophagic action. Collectively, these findings indicate that ATG3 is a novel protein implicated in the development of steatosis. We show that autophagy-related gene 3 (ATG3) contributes to the progression of non-alcoholic fatty liver disease in humans and mice. Hepatic knockdown of ATG3 ameliorates the development of NAFLD by stimulating mitochondrial function. Thus, ATG3 is an important factor implicated in steatosis. [Display omitted] • ATG3 levels are elevated in the livers of mice and patients with NAFLD. • Inhibition of ATG3 in human hepatocytes and in mouse liver ameliorates steatosis by stimulating SIRT1, CPT1a, and mitochondrial function. • Hepatic knockdown of SIRT1 or CPT1a blunts the ability of ATG3 inhibition to increase mitochondrial activity and to alleviate steatosis. [ABSTRACT FROM AUTHOR]

To assess the effects of starvation on Synechogobius hasta intestinal function and morphology, fish were starved for 3, 7 and 14 days, followed by the measurement of histological, physiological and transcriptional responses in the intestine. Intestinal length was significantly lower in S. hasta starved for 7 and 14 days (p < 0.05). Intestinal amylase activity was significantly decreased upon fasting (p < 0.05), whereas a lower level of intestinal lipase activity was not observed until the end of the trial. After 7‐day starvation, the intestine of starved S. hasta exhibited exfoliated villus cells, increased vacuoles and widened cell interstices. Regarding the expression of lipid metabolism‐associated genes, poststarvation transcript levels of lipoprotein lipase, carnitine palmitoyltransferase 1 a and fatty acid transport protein 1 significantly increased with longer food deprivation periods (p < 0.05). Meanwhile, downregulation of stearoyl‐CoA desaturase 1 was observed in the intestine upon starvation (p < 0.05). In summary, prolonged starvation (>14 days) not only disrupted the intestinal structure, which may further weaken digestive potential, but also attenuated intestinal lipid deposition by diminishing lipid biosynthesis, as well as upregulating lipolysis and fatty acid transport. Therefore, our findings provide preliminary data for further characterization of metabolic traits in starved S. hasta, which may have important implications for determining the appropriate starvation time applied in fasting/re‐feeding regimes, as well as the sustainable development of S. hasta and other fish. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the effects of lipid emulsions on carnitine palmitoyltransferase I (CPT-I), carnitine acylcarnitine translocase (CACT), carnitine palmitoyltransferase II (CPT-II), and the mitochondrial dysfunctions induced by toxic doses of local anesthetics in H9c2 rat cardiomyoblasts. The effects of local anesthetics and lipid emulsions on the activities of CPT-I, CACT, and CPT-II, and concentrations of local anesthetics were examined. The effects of lipid emulsions, N-acetyl-L-cysteine (NAC), and mitotempo on the bupivacaine-induced changes in cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential (MMP), and intracellular calcium levels were examined. CACT, without significantly altering CPT-I and CPT-II, was inhibited by toxic concentration of local anesthetics. The levobupivacaine- and bupivacaine-induced inhibition of CACT was attenuated by all concentrations of lipid emulsion, whereas the ropivacaine-induced inhibition of CACT was attenuated by medium and high concentrations of lipid emulsion. The concentration of levobupivacaine was slightly attenuated by lipid emulsion. The bupivacaine-induced increase of ROS and calcium and the bupivacaine-induced decrease of MMP were attenuated by ROS scavengers NAC and mitotempo, and the lipid emulsion. Collectively, these results suggested that the lipid emulsion attenuated the levobupivacaine-induced inhibition of CACT, probably through the lipid emulsion-mediated sequestration of levobupivacaine. [ABSTRACT FROM AUTHOR]

Background& Aims: Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism.Approach& Results: Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice.Conclusions: Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD. [ABSTRACT FROM AUTHOR]

Objective: This study aims to analyze the alteration of carnitine profile in the small intestine of abdominal irradiation-induced intestinal injury rats and explore the possible reason for the altered carnitine profile. Methods: The abdomens of 15 male Sprague Dawley (SD) rats were irradiated with 0, 10, and 15 Gy of 60 Co gamma rays. The carnitine profile in the small intestine and plasma samples of SD rats at 72 h after abdominal irradiated with 0 Gy or 10 Gy of 60 Co gamma rays were measured by targeted metabolomics. The changes of fatty acid β-oxidation (FAO), including the expression of carnitine palmitoyltransferase 1 (CPT1) and acyl-CoA dehydrogenases, were analyzed in the small intestine samples of SD rats after exposed to 0, 10, and 15 Gy groups. Results: There were eleven acylcarnitines in the small intestine and fourteen acylcarnitines in the plasma of the rat model significantly enhanced, respectively (P < .05). The expression level and activity of CPT1 in the small intestine were remarkably increased (P < .05), and the activity of acyl-CoA dehydrogenase in the small intestine was noticeably reduced (P < .01) after abdominal irradiation. Conclusion: The enhanced acylcarnitine levels in the small intestine of abdominal irradiation rats might relate to the FAO pathway disequilibration. [ABSTRACT FROM AUTHOR]

An 8-week feeding trial was conducted to explore the effects of replacement of dietary fishmeal by cottonseed protein concentrate (CPC) on growth performance, liver health, and intestine histology of largemouth bass. Four isoproteic and isolipidic diets were formulated to include 0, 111, 222, and 333 g/kg of CPC, corresponding to replace 0% (D1), 25% (D2), 50% (D3), and 75% (D4) of fishmeal. Two hundred and forty largemouth bass (15.11 ± 0.02 g) were randomly divided into four groups with three replicates per group. During the experiment, fish were fed to apparent satiation twice daily. Results indicated that CPC could replace up to 50% fishmeal in a diet for largemouth bass without significant adverse effects on growth performance. However, weight gain rate (WGR), specific growth rate (SGR), feed efficiency (FE), and condition factor (K) of the largemouth bass were significantly decreased when 75% of dietary fishmeal that was replaced by CPC. The whole body lipid content was increased with the increasing of dietary CPC levels. Oil red O staining results indicated that fish fed the D4 diet showed an aggravated fat deposition in the liver. Hepatocytes exhibited serious degeneration, volume shrinkage, and inflammatory cells infiltration in the D4 group. Intestinal villi appeared shorter and sparse with severe epithelial damage in the D4 group. The transcription levels of anti-inflammatory cytokines, such as transforming growth factor β (tgf- β), interleukin 10 (il-10), and interleukin 11 β (il-11 β), were downregulated in the D4 group. The lipid metabolism-related genes carnitine palmitoyl transferase 1 (cpt1), peroxisome proliferator-activated receptor α (ppar α), and target of rapamycin (TOR) pathway were also significantly downregulated in the D4 group. It was concluded that suitable replacement of fishmeal by less than 222 g CPC/kg diet had a positive effect on growth performance of fish, but an excessive substitution of 75% fishmeal by CPC would lead to the suppressed growth, liver inflammation, and intestinal damage of largemouth bass. [ABSTRACT FROM AUTHOR]

Inflammatory osteolysis is usually linked to the activation of proinflammatory macrophage and the consequent excessive osteoclast formation. Emerging evidence indicates that agents or drugs targeting lipid metabolism in macrophages might be potential in the prevention and treatment of osteolysis. d -mannose, as a natural-existed metabolic regulator, exerts strong effects on attenuating osteopenia and inflammation. However, whether d -mannose is therapeutically effective on osteolysis and whether a metabolic mechanism counts for the effect remain to be addressed. Here, by using an in vivo lipopolysaccharide (LPS)-induced inflammatory osteolysis mouse model as well as an in vitro LPS-induced inflammatory macrophage culture system, we show that d -mannose attenuates inflammatory osteolysis and inhibits excessive osteoclastogenesis by reversing the LPS-induced activation of proinflammatory macrophage. Mechanically, d -mannose recovers LPS-suppressed Cpt1a transcription and promotes lipid metabolism of macrophage. Treatment with etomoxir, an inhibitor of CPT1A, abolishes the effects of d -mannose on LPS-treated macrophage in vitro and eliminates its protection against osteolysis in vivo. Collectively, our results imply that d -mannose attenuates LPS-induced osteolysis by manipulating CPT1A-mediated lipid metabolism in macrophages. Our results disclose the unrecognized utilization of d -mannose as an effective intervention against inflammatory osteolysis and provide evidence to manage inflammatory scenarios by therapeutically targeting lipid metabolism in macrophage. [Display omitted] • d -Mannose effectively alleviates LPS-induced calvarial osteolysis and inhibits excessive osteoclastogenesis. • d -mannose reverses the LPS-induced macrophage switch to proinflammatory (M1) subtype. • d -mannose suppresses excess lipid storage in inflammatory macrophages. • CPT1A-manipulated lipid metabolism in macrophage mediates the role of d -mannose in osteolysis. [ABSTRACT FROM AUTHOR]

A 75-day rearing trial was designed to study the response of juvenile Megalobrama amblycephala to dietary methionine (Met) levels. Three practical diets with graded Met levels (0.40%, 0.84% and 1.28% dry matter) were prepared to feed the juvenile fish. The results showed that the 0.84% Met diet significantly improved the growth compared with 0.40% diets. Compared with 0.84% and 1.28% Met, 0.40% Met significantly increased the hepatic lipid content, while decreasing the muscular lipid and glycogen contents. 0.40% Met decreased the protein levels of phospho-Eukaryotic initiation factor 4E binding protein-1 (p-4e-bp1), 4e-bp1 and Ribosomal protein S6 kinase 1 in the liver, compared with 0.84% diet, while an increasing trend was observed in the muscle. Met supplementation tended to decrease and increase lipid synthesis in the liver and muscle, respectively, via changing mRNA levels of sterol regulatory element-binding protein 1, fatty acid synthetase and acetyl-CoA carboxylase. 1.28% dietary Met promoted fatty acid β-oxidation and lipolysis in both the liver and muscle by increasing carnitine palmitoyl transferase 1, peroxisome proliferator activated receptor alpha, lipoprotein lipase and lipase mRNA levels. Compared with 0.40% and 0.84% dietary Met, 1.28% Met enhanced the mRNA levels of hepatic gluconeogenesis related genes phosphoenolpyruvate carboxykinase (pepck), and glucose-6-phosphatase, and muscular glycolysis related genes phosphofructokinase (pfk), and pyruvate kinase (pk). The mRNA levels of hepatic pfk, pk and glucokinase were markedly downregulated by 1.28% Met compared with 0.84% level. Muscular pepck, glycogen synthase, and hepatic glucose transporters 2 mRNA levels were induced by 1.28% Met. Generally, deficient Met level decreased the growth of juvenile Megalobrama amblycephala, and the different nutrient metabolism responses to dietary Met were revealed in the liver and muscle. [ABSTRACT FROM AUTHOR]

Background: The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD). Results: As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet. Conclusion: We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR. [ABSTRACT FROM AUTHOR]

• CACT and CPT2 deficiencies can be missed or misdiagnose if only individual acylcarnitine were interpreted without the acylcarnitine ratios. • CACT and CPT2 deficiency patients may present with marked hyperammonemia which may mimic the Urea cycle defect biochemically. • Three novel mutations at c.109C > T p. (Arg37*) in exon 2, c.706C > T p. (Arg236*) in exon 7 of SLC25A20 gene and another novel mutation c.1073 T > G p. (Leu358Arg) in exon 4 of CPT2 gene were found in this study. • The use of the C16 + C18:1/C2 acylcarnitine ratio in dried blood spot in our experience improves the diagnostic specificity for CACT/CPT2 deficiencies. Carnitine-acylcarnitine Translocase (CACT) deficiency (OMIM 212138) and carnitine palmitoyl transferase 2 (CPT2) deficiency (OMIM 60065050) are rare inherited disorders of mitochondrial long chain fatty acid oxidation. The aim of our study is to review the clinical, biochemical and molecular characteristics in children diagnosed with CACT and CPT2 deficiencies in Malaysia. This is a retrospective study. We reviewed medical records of six patients diagnosed with CACT and CPT2 deficiencies. They were identified from a selective high-risk screening of 50,579 patients from January 2010 until Jun 2020. All six patients had either elevation of the long chain acylcarnitines and/or an elevated (C16 + C18:1)/C2 acylcarnitine ratio. SLC25A20 gene sequencing of patient 1 and 6 showed a homozygous splice site mutation at c.199–10 T > G in intron 2. Two novel mutations at c.109C > T p. (Arg37*) in exon 2 and at c.706C > T p. (Arg236*) in exon 7 of SLC25A20 gene were found in patient 2. Patient 3 and 4 (siblings) exhibited a compound heterozygous mutation at c.638A > G p. (Asp213Gly) and novel mutation c.1073 T > G p. (Leu358Arg) in exon 4 of CPT2 gene. A significant combined prevalence at 0.01% of CACT and CPT2 deficiencies was found in the symptomatic Malaysian patients. The use of the (C16 + C18:1)/C2 acylcarnitine ratio in dried blood spot in our experience improves the diagnostic specificity for CACT/CPT2 deficiencies over long chain acylcarnitine (C16 and C18:1) alone. DNA sequencing for both genes aids in confirming the diagnosis. [ABSTRACT FROM AUTHOR]

Xylooligosaccharide (XOS) is a source of prebiotics with multiple biological activities. The present study aimed to investigate the effects of XOS on mice fed a high-fat diet. Mice were fed either a normal diet or a high-fat diet supplemented without or with XOS (250 and 500 mg/kg), respectively, for 12 weeks. The results showed that the XOS inhibited mouse weight gain, decreased the epididymal adipose index, and improved the blood lipid levels, including triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels. Moreover, XOS reduced the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and alleviated the damage to the liver caused by the high-fat diet. XOS also reduced hyperlipidemia-associated inflammatory responses. Additionally, quantitative real-time polymerase chain reaction results showed that XOS intervention activated the AMP-activated protein kinase (AMPK) pathway to regulate the fat synthesis, decomposition, and β oxidation; upregulated the mRNA expression levels of carnitine palmitoyl transferase 1 (CPT-1), peroxisome proliferator–activated receptors α (PPAR-α), and cholesterol 7-alpha hydroxylase (CYP7A1); and downregulated the mRNA expression levels of acetyl-CoA carboxylase (ACC), CCAAT/enhancer-binding protein alpha (C/EBPα), and lipoprotein lipase (LPL). On the other hand, XOS enhanced the mRNA expression levels of zonula occludens-1 (ZO-1), occludin, and claudin-1 in the small intestine; increased the strength of the intestinal barrier; and optimized the composition of the intestinal microbiota. Therefore, it was concluded that XOS regulated the intestinal barrier, changed the intestinal microecology, and played an important role in preventing hyperlipidemia through the unique anatomical advantages of the gut–liver axis. [ABSTRACT FROM AUTHOR]

Objective To observe the changes of parameters associated with liver fatty acid metabolism in rats under different hypoxia exposure times at medium-altitude area. Methods Sixty SD rats were randomly divided into the following six groups : the control group, 1 d group, 3 d group, 7 d group, 15 d group, and 30 d group. Rats in the control group were kept in the animal room( 400 m above sea level)of the Animal Experiment Center of the Medical Department of Xi an Jiaotong University for 30 days, while rats in the 1 d group, 3 d group, 7 d group, 15 d group, and 30 d group were kept and fed in the animal room( 2 260 m above sea level)of high altitude medical center of the Medical Department of Xi an Jiaotong University for 1, 3, 7, 15, and 30 d, respectively. Detecting the blood parameters alanine transaminase(ALT), non-esterified fatty acids( NEF A)and ketone bodies(KB)in the liver tissues. The gene and protein expression levels of AMP-activated protein kinase( AMPK), acetyl coenzyme A carboxylase 1( ACC-1), carnitine palmitoyltransferase I( CPT-1), and hypoxia-inducible factor 1 a( HIF-1 a)in the liver tissues were detected. Results There was no significant difference in the ALT, KB, or NEFA among groups(all P > 0. 05). The expression of AMPK mRNA in the liver tissues of the control group was higher than that of the 1 d group, 3 d group, 7 d group, 15 d group and 30 d group (all P < 0. 05). The expression of ACC-1 mRNA and CPT-1 mRNA in the 15 d group was at the lowest level, but the expression of the 30 d group increased to that of the control group. The expression levels of HIF -1 a mRNA in the 1 d group, 3 d group, 7 d group and 15 d group were significantly higher than that of the control group, and the expression of HIF-la in the 30 d group decreased to that of the control group. The AMPK protein expression levels of the control group and 1 d group were higher than those of the 3 d group, 7 d group, 15 d group, and 30 d group (all P < 0. 05 ). The protein expression levels of ACC-1, CPT-1, and HIF -1 a in the 3 d group were higher than those of the control group, 1 d group, 7 d group, 15 d group, and 30 d group (all P < 0. 05). Conclusions There are differences in fatty acid metabolism between the medium-altitude area and the plain area. The fatty acid synthesis and oxidative metabolism in the acute exposure period of the medium- altitude area show a transient enhancement; on the 7th day of exposure, with the rapid improvement of hypoxia, they return to the level of the plain area. [ABSTRACT FROM AUTHOR]

Lipid metabolism involves multiple biological processes. As one of the most important lipid metabolic pathways, fatty acid oxidation (FAO) and its key rate-limiting enzyme, the carnitine palmitoyltransferase (CPT) system, regulate host immune responses and thus are of great clinical significance. The effect of the CPT system on different tissues or organs is complex: the deficiency or over-activation of CPT disrupts the immune homeostasis by causing energy metabolism disorder and inflammatory oxidative damage and therefore contributes to the development of various acute and chronic inflammatory disorders and cancer. Accordingly, agonists or antagonists targeting the CPT system may become novel approaches for the treatment of diseases. In this review, we first briefly describe the structure, distribution, and physiological action of the CPT system. We then summarize the pathophysiological role of the CPT system in chronic obstructive pulmonary disease, bronchial asthma, acute lung injury, chronic granulomatous disease, nonalcoholic fatty liver disease, hepatic ischemia–reperfusion injury, kidney fibrosis, acute kidney injury, cardiovascular disorders, and cancer. We are also concerned with the current knowledge in either preclinical or clinical studies of various CPT activators/inhibitors for the management of diseases. These compounds range from traditional Chinese medicines to novel nanodevices. Although great efforts have been made in studying the different kinds of CPT agonists/antagonists, only a few pharmaceuticals have been applied for clinical uses. Nevertheless, research on CPT activation or inhibition highlights the pharmacological modulation of CPT-dependent FAO, especially on different CPT isoforms, as a promising anti-inflammatory/antitumor therapeutic strategy for numerous disorders. [ABSTRACT FROM AUTHOR]