Search

Ames dwarf mice (df/df) display delayed aging relative to their normal (N) siblings, living approximately 40-60 % longer. As such, investigating the mechanisms that enable these organisms to have extended lifespan is useful for the development of interventions to slow aging and deter age-related disease. Nonalcoholic fatty liver disease (NAFLD) is a condition that is characterized by the accumulation of excess adipose tissue in the liver. Previous studies highlight the potential of calorie restriction (CR) in promoting longevity, but little is known about its effects on the biomolecular processes that govern NAFLD. In this study, we examined the role of 6-month CR on genes regulating lipid metabolism in the livers of long-living df/df mice and their N littermates. Importantly, our findings showed significant downregulation of miR-34a-5p in N-CR mice and df/df mice regardless of dietary regimen. Alongside, our RT-PCR results indicated that downregulation of miR-34a-5p is correlated with the expression of metabolism-associated mRNAs involved in modulating the processes of de novo lipogenesis (DNL), fatty acid oxidation (FAO), very-low density lipoprotein transport (VLDL-T), and reverse cholesterol transport (RCT). To further verify the role of miR-34a-5p in regulating metabolic processes, we transfected the human liver cancer (HepG2) cell line with miR-34a mimic, and studied its effect on direct targets Sirt1, Ampk, and Ppara as well as downstream lipid transport regulating genes. Our findings suggest that CR and df/df life extending mutation are robust drivers of the miR-34a-5p signaling pathway and prevent the pathogenesis of age-related diseases by improving overall lipid homeostasis., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists., (Copyright © 2024. Published by Elsevier Inc.)

Investigating and identifying pathogenic molecules of non-alcoholic fatty liver disease (NAFLD) has become imperative, which would serve as effective targets in the future. We established high-fat diet (HFD)-induced NAFLD model in mice and palmitic acid (PA)-induced model in mouse AML12 cells. The level of miR-218-5p was examined by qRT-PCR, and Elovl5 was identified as the potential target gene of miR-218-5p. The binding relationship between miR-218-5p and Elovl5 was validated by double luciferase reporter gene assay, and inhibition/overexpression of miR-218-5p in vitro. The functional mechanisms of miR-218-5p/Elovl5 in regulating lipogenesis in NAFLD were investigated in vivo and in vitro through gain- and loss-of-function studies. MiR-218-5p was significantly increased, and Elovl5 was decreased in model group. According to the double luciferase reporter and gene interference experiments in AML12 cells, Elovl5 was a target gene of miR-218-5p and its expression was regulated by miR-218-5p. The SREBP1-mediated lipogenesis signaling pathway regulated by Elovl5 was upregulated in model group. Moreover, silencing of miR-218-5p significantly upregulated Elovl5 expression, and suppressed SREBP1 signaling pathway in PA-induced AML-12 cells. Correspondingly, the cell injury, elevated TC, TG contents and lipid droplet accumulation were ameliorated. Furthermore, the effect of miR-218-5p on lipogenesis in vitro and in vivo was obstructed by si-Elovl5, implicating that miR-218-5p promotes lipogenesis by targeting ELOVL5 in NAFLD. miR-218-5p could promote fatty acid synthesis by targeting Elovl5, thereby accelerating the development of NAFLD, which is one of the key pathogenic mechanisms of NAFLD and provides a new molecular target for the management of NAFLD., 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 Inc. All rights reserved.)

Long non-coding RNAs (lncRNAs) have been demonstrated to play vital roles in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). However, their biological roles and function mechanisms in NAFLD remain largely unknown. In this study, we found that Gm28382 may be a potential pathogenic lncRNA of NAFLD and highly expressed in NAFLD through RNA-seq. Overexpression of Gm28382 significantly enhanced the lipid accumulation in AML12 cells, whereas Gm28382 silencing reduced lipogenesis both in palmitic acid (PA)-induced AML12 cells and high fat diet (HFD)-induced mice. Then, bioinformatics were employed to speculate the potential interacting genes of Gm28382, and found that Gm28382 may regulate ChREBP expression through binding with miR-326-3p. Fluorescence in situ hybridization (FISH), dual luciferase reporter assay, immunofluorescence RNA pull-down and RNA immunoprecipitation (RIP) assays were used to validate the binding and targeting relationship of these genes, and we confirmed that Gm28382 competitively binds to miR-326-3p to increase ChREBP expression as a ceRNA. Mechanistically, overexpression of Gm28382 upregulated the ChREBP-mediated lipid synthesis signaling pathway, but the function was sabotaged by miR-326-3p deletion or ChREBP overexpression. Furthermore, in PA-challenged AML12 cells or HFD-induced mice, silencing of Gm28382 reversed the aberrant ChREBP signaling pathway and lipid accumulation, whereas ChREBP overexpression or liver-specific silencing of miR-326-3p blocked this function of Gm28382. Collectively, these findings reveal a critical role of Gm28382 in the promotion of lipogenesis in NAFLD by regulating the ChREBP signaling pathway through interaction with miR-326-3p, which could serve as a potential therapeutic target for NAFLD treatment., 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 Elsevier B.V. All rights reserved.)

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is characterized by intrahepatic triglyceride accumulation and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. Hepatic de novo lipogenesis (DNL), activated by glucose and insulin, is a central pathway contributing to early-stage development of MASLD. The emerging global prevalence of MASLD highlights the urgent need for pharmaceutical intervention to combat this health threat. However, the identification of novel drugs that could inhibit hepatic DNL is hampered by a lack of reliable, insulin-sensitive, human, in vitro, hepatic models. Here, we report human skin stem cell-derived hepatic cells (hSKP-HPC) as a unique in vitro model to study insulin-driven DNL (iDNL), evidenced by both gene expression and lipid accumulation readouts. Insulin-sensitive hSKP-HPC showed increased sterol regulatory element-binding protein 1c (SREBP-1c) expression, a key transcription factor for DNL. Furthermore, this physiologically relevant in vitro human steatosis model allowed both inhibition and activation of the iDNL pathway using reference inhibitors and activators, respectively. Optimisation of the lipid accumulation assay to a high-throughput, 384-well format enabled the screening of a library of annotated compounds, delivering new insights on key players in the iDNL pathway and MASLD pathophysiology. Together, these results establish the value of the hSKP-HPC model in preclinical development of antisteatotic drugs to combat MASLD., Competing Interests: Declaration of competing interest M. Vrints, T. Van Eeckhoutte, M. Jans, J. Van Der Schueren and F. Beirinckx are employed at Galapagos NV. K. Buyl, R. Fernando, T. Desmae, J. Boeckmans, R. M. Rodrigues, V. De Boe, V. Rogiers, J. De Kock and T. Vanhaecke declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Accumulating evidence suggests that de novo lipogenesis is a typical characteristic facilitating nonalcoholic fatty liver disease (NAFLD) progression. Gallic acid (GA) is a naturally occurring phenolic acid with metabolic disease-related clinical significance and preclinical benefits. This study aimed to evaluate the anti-steatotic potentials of GA in a fructose-induced NAFLD mouse model featuring a hepatic lipogenic phenotype. The results revealed that GA alleviated hepatic steatosis, oxidative stress, and inflammatory response in fructose-fed mice. Mechanistically, GA treatment restored AMP-activated protein kinase α (AMPKα) phosphorylation, resulting in downregulations of pro-lipogenic factors, including sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthetase (FASN), and acetyl-CoA carboxylase (ACC), in hepatocytes of mice and in vitro. Furthermore, computational docking analysis indicated that GA could directly interact with AMPKα/β subunits to stabilize its activation. These results suggest that GA ameliorates fructose-induced hepatosteatosis by restraining hepatic lipogenesis via AMPK-dependent suppression of the SREBP-1/ACC/FASN cascade. Altogether, this study demonstrates that GA supplement may be a promising therapeutic strategy in NAFLD, especially in the subset with enhanced hepatic lipogenesis., 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 © 2022 Elsevier B.V. All rights reserved.)

The oleaginous fungus Mortierella alpina has distinct advantages in long-chain PUFAs production, and it is the only source for dietary arachidonic acid (ARA) certificated by FDA and European Commission. This review provides an overall introduction to M. alpina, including its major research methods, key factors governing lipid biosynthesis, metabolic engineering and omics studies. Currently, the research interests in M. alpina focus on improving lipid yield and fatty acid desaturation degree by enhancing fatty acid precursors and the reducing power NADPH, and genetic manipulation on PUFAs synthetic pathways is carried to optimise fatty acid composition. Besides, multi-omics studies have been applied to elucidate the global regulatory mechanism of lipogenesis in M. alpina. However, research challenges towards achieving a lipid cell factory lie in strain breeding and cost control due to the coenocytic mycelium, long fermentation period and insufficient conversion rate from carbon to lipid. We also proposed future research goals based on a multilevel regulating strategy: obtaining ideal chassis by directional evolution and high-throughput screening; rewiring central carbon metabolism and inhibiting competitive pathways by multi-gene manipulation system to enhance carbon to lipid conversion rate; optimisation of protein function based on post-translational modification; application of dynamic fermentation strategies suitable for different fermentation phases. By reviewing the comprehensive research progress of this oleaginous fungus, we aim to further comprehend the fungal lipid metabolism and provide reference information and guidelines for the exploration of microbial oils from the perspectives of fundamental research to industrial application., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cytochromes P450 (CYPs) are a multigene superfamily of constitutively expressed and inducible enzymes responsible for the detoxification of many endogenous and exogenous compounds and for the metabolism of numerous medications. The cytochrome P450 2F2 (CYP2F2) subfamily is preferentially expressed in the respiratory tract, but its functional role in adipocytes has never been explored. We found that CYP2F2 was highly expressed during the differentiation of the C3H10T1/2 murine mesenchymal stem cells to adipocytes and here we have explored its functional role in adipocytes. The expression of thermogenic marker proteins such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), PR domain containing 16 (PRDM16), and uncoupling protein 1 (UCP1) and beige-fat specific genes were significantly increased in Cyp2f2-deficient 3T3-L1 adipocytes. Moreover, Cyp2f2 silencing led to reduced adipogenesis and lipogenesis, and enhanced lipid catabolism through the increased expression of lipolytic and fatty acid oxidative enzymes. A mechanistic study to identify molecular signals for CYP2F2-mediated negative regulation in the browning of white adipocytes revealed that CYP2F2 impairs the beta-3 adrenergic receptor (β3-AR) activation as well as its downstream regulators including protein kinase A (PKA), p38 mitogen-activated protein kinase (p38 MAPK), and activating transcription factor 2 (ATF2). This data provides evidence that CYP2F2 is a negative regulator of lipid catabolism and browning in white adipocytes, suggesting that inhibitors of CYP2F2 could be potential drugs for the treatment of obesity with a focus on enhancing energy expenditure., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is the major type of primary liver cancer and a leading cause of cancer-related deaths worldwide. Cinobufotalin (CBF) is extracted from the skin secretion of the giant toad and clinically used for the treatment of liver cancer, but its molecular mechanism of anti-cancer in HCC has not yet been elucidated. Here, we showed CBF effectively promoted cell apoptosis, induced cell cycle G2-M arrest, inhibited cell proliferation and lipogenesis. Consistently, the lipogenesis ability of xenograft examined by 11 C-acetate micro-PET/CT imaging, and the tumor growth rate was notably declined in a centration-dependent manner. The fatty acid profiles showed saturated and mono-unsaturated fatty acid significantly decreased after CBF treatment. Mechanistically, CBF selectively inhibited the expression of SREBP1 and interacted with SREBP1 to prevent it from sterol regulatory elements (SREs), thus inhibiting the expression of lipogenic enzymes. Collectively, our study demonstrates that CBF is a potent native compound that remarkably inhibits HCC lipogenesis and tumorigenesis. CBF may possess this therapeutic potential though interfering with de novo lipid synthesis via SREBP1., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Prostate cancer (PCa) is one of the most fatal malignant tumors that occurs in the prostate epithelium, especially in older men, the mortality of which ranks sixth among all cancer-related deaths. It has been urgently needed to elucidate the pathogenesis of PCa and provide promising therapeutic targets for PCa treatment. The Sterol O-acyltransferase 1 (SOAT1), cholesterol metabolism enzyme, was widely expressed in various cancer tissues, resulting in cancer progression. SOAT1 has been demonstrated to be highly expressed in prostate cancer tissues, whereas the underlying mechanism has not been elucidated. Herein, we found the expression of SOAT1 was elevated in human PCa tissues, which demonstrated SOAT1 level was correlated with lymph node metastasis (p = 0.006), clinical stage (p = 0.032), grading (p = 0.036), and Gleason score (p = 0.030) of PCa patients. In addition, we revealed that SOAT1 promoted proliferation and liposynthesis of PCa cells by targeting Stearoyl-CoA Desaturase 1 (SCD1). Our data further confirmed that SCD1 overexpression reversed the proliferation and liposynthesis defects caused by SOAT1 depletion in PCa cells, however, SOAT1 depletion inhibited tumor growth of PCa cells in mice. We further found SOAT1 contributed to the progression of PCa via SREBF1 pathway. Taken together, our data revealed the mechanism underlying SOAT1 promoting PCa progression in vitro and in vivo., (Copyright © 2021 Elsevier Inc. All rights reserved.)

There is no known single therapeutic drug for treating hypercholesterolemia that comes with negligible systemic side effects. In the current study, using next generation RNA sequencing approach in mouse embryonic fibroblasts we discovered that two structurally related flavonoid compounds. Apigenin and Chrysin exhibited moderate blocking ability of multiple transcripts that regulate rate limiting enzymes in the cholesterol biosynthesis pathway. The observed decrease in cholesterol biosynthesis pathway correlated well with an increase in transcripts involved in generation and trafficking of ketone bodies as evident by the upregulation of Bdh1 and Slc16a6 transcripts. The hypocholesterolemic potential of Apigenin and Chrysin at higher concentrations along with their ability to generate ketogenic substrate especially during embryonic stage is useful or detrimental for embryonic health is not clear and still debatable. Our study will serve as a steppingstone to further the investigation in whole animal studies and also in translating this knowledge to human studies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Citrus fruits contain an abundance of nutrients, including vitamins C and B 6 and hesperidin, which attribute to its beneficial health effects. Previously, kimchi with Jeju citrus concentrate (CK) elicited anti-obesity effects in 3T3-L1 adipocytes. Here, we aimed to investigate whether CK exhibits anti-obesity effects by reducing serum and hepatic lipid concentrations and anti-obesity-associated gene expression in high-fat diet (HFD)-induced obese C57BL/6N mice. Low-dose CK (LDCK, 50 mg/kg) and high-dose CK (HDCK, 200 mg/kg) were orally administered 3 times per week over 8 weeks with HFD diet. Body weight gain, food efficiency ratio, and tissue weight were measured. Serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance, leptin, and adiponectin concentrations were also assessed. The effect of CK on the lipid profile and lipid accumulation was analyzed. Body and white adipose tissue masses were significantly lower in the LDCK and HDCK groups than in the HFD group. Orally administered CK significantly decreased serum lipid, fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance, glutamic oxaloacetic transaminase, and glutamic pyruvic transaminase levels. Hepatic lipid content also decreased in the LDCK and HDCK groups. Serum leptin concentrations decreased, whereas serum adiponectin concentrations increased, confirming the anti-obesity effects of LDCK and HDCK. The decrease of hepatic vacuoles and stained lipid droplets indicated inhibition of lipid accumulation. These results support the hypothesis that CK exhibits anti-obesity effects in vivo by reducing lipid accumulation and by regulating anti-obesity-related genes., (Copyright © 2020. Published by Elsevier Inc.)

Maternal fructose consumption during pregnancy and lactation is associated with metabolic dysregulation in offspring. We tested the hypothesis that fish oil (FO) supplementation during pregnancy and lactation improves fructose-induced metabolic dysregulation in postpartum dams and offspring mice. We therefore aimed to determine the effects of FO supplementation on metabolic disruption in neonatal mice and dams induced by a maternal high-fructose diet (HFrD). The weight of the offspring of dams fed with HFrD on postnatal day 5 was significantly low, but this was reversed by adding FO to the maternal diet. Feeding dams with HFrD significantly increased plasma concentrations of triglycerides, uric acid, and total cholesterol, and decreased free fatty acid concentrations in offspring. Maternal supplementation with FO significantly suppressed HFrD-induced hypertriglyceridemia and hyperuricemia in the offspring. Maternal HFrD induced remarkable mRNA expression of the lipogenic genes Srebf1, Fasn, Acc1, Scd1, and Acly in the postpartum mouse liver without affecting hepatic and plasma lipid levels. Although expression levels of lipogenic genes were higher in the livers of postpartum dams than in those of nonmated mice, HFrD feeding increased the hepatic lipid accumulation in nonmated mice but not in postpartum dams. These findings suggest that although hepatic lipogenic activity is higher in postpartum dams than nonmated mice, the lipid consumption is enhanced in postpartum dams during pregnancy and lactation. Maternal FO supplementation obviously suppressed the expression of these lipogenic genes. These findings coincide with reduced plasma triglyceride concentrations in the offspring. Therefore, dietary FO apparently ameliorated maternal HFrD-induced dyslipidemia in offspring by suppressing maternal lipogenic gene expression and/or neonatal plasma levels of uric acid., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus, cardiovascular disease, and all-cause mortality. Previously, we demonstrated that lipocalin-type prostaglandin D 2 synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in mediating NAFLD utilizing L-PGDS knockout (KO) and control C57BL/6 mice fed either low fat (LFD) or high fat diet (HFD) for 14 weeks. Our present study demonstrates that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster and eventually progress to the more severe non-alcoholic steatohepatitis (NASH). We found increased lipid accumulation in the liver of KO mice over time on both diets, as compared to control mice. The L-PGDS KO mice showed elevated fasting glucose and insulin levels and developed insulin resistance on both LFD and HFD. Lipogenesis marker proteins such as SREBP-1c and LXRα were increased in L-PGDS KO mice after 14 weeks on both diets, when compared to control mice. We replicated our in vivo findings in vitro using HepG2 cells treated with a combination of free fatty acids (oleic and palmitic acid) and exposure to a L-PGDS inhibitor and prostaglandin D 2 receptor (DP1) antagonists. We conclude that the absence or inhibition of L-PGDS results in dyslipidemia, altered expression of lipogenesis genes and the acceleration of NAFLD to NASH, independent of diet and obesity. We propose L-PGDS KO mice as a useful model to explore the pathogenesis of NAFLD and NASH, and L-PGDS as a potential therapeutic target for treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In previous studies, we showed two consistent findings regarding the functional relationship between hepatitis B virus (HBV) gene expression and hepatic lipid accumulation. One is that HBV X (HBx) protein expression induces hepatic lipid accumulation via specific transcriptional activation. The other is that hepatic rich lipids increase HBV gene expression. A variety of transcription factors, including nuclear receptors have been defined as regulators of HBV promoters and enhancers. However, the association between these metabolic events and HBV gene expression remains to be clearly elucidated. Here, we showed that lipid accumulation due to mitochondrial dysfunction is associated with an increase in HBV gene expression. Saturated fatty acids increase the expression of lipogenic factors cooperated with C/EBPα and LXRα. In addition, activation of PPARγ and SREBP-1 by fatty acids derived from hepatic lipid accumulation was found to increase HBV gene expression through mitochondrial dysfunction. These results provide that metabolic changes in the hepatic cells play a critical role in the HBV gene induction., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Meloidogyne incognita is a polyphagous plant-parasitic nematode that causes considerable yield loss in agricultural and horticultural crops. The management options available for M. incognita are extremely limited. Here we identified and characterised a M. incognita homolog of Caenorhabditis elegans sterol-binding protein (Mi-SBP-1), a transcriptional regulator of several lipogenesis pathway genes, and used RNA interference-mediated gene silencing to establish its utility as a target for the management of M. incognita. Mi-sbp-1 is predicted to be a helix-loop-helix domain containing DNA binding transcription factor, and is present in the M. incognita genome in three copies. The RNA-Seq analysis of Mi-sbp-1 silenced second stage juveniles confirmed the key role of this gene in lipogenesis regulation in M. incognita. In vitro and host-induced gene silencing of Mi-sbp-1 in M. incognita second stage juveniles resulted in loss of nematodes' ability to utilise the stored fat reserves, slower nematode development, and reduced parasitism on adzuki bean and tobacco plants. The multiplication factor for the Mi-sbp-1 silenced nematodes on adzuki bean plants was reduced by 51% compared with the control nematodes in which Mi-sbp-1 was not silenced. Transgenic expression of the double-stranded RNA construct of the Mi-sbp-1 gene in tobacco plants caused 40-45% reduction in M. incognita multiplication, 30-43.8% reduction in the number of egg masses, and 33-54% reduction in the number of eggs per egg mass compared with the wild type control plants. Our results confirm that Mi-sbp-1 is a key regulator of lipogenesis in M. incognita and suggest that it can be used as an effective target for its management. The findings of this study can be extended to develop methods to manage other economically important parasitic nematodes., (Copyright © 2019 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.)

Cholesterol, via sterol regulatory element-binding protein (SREBP) transcription factors, activates or represses genes involved in its hepatic biosynthetic pathway, and also modulates the expression of hepatocyte mitochondrial aquaporin-8 (mtAQP8), a channel that can function as peroxiporin by facilitating the transmembrane diffusion of H 2 O 2 . Here we tested the hypothesis that mtAQP8 is involved in the SREBP-mediated regulation of hepatocyte cholesterol biosynthesis. Using human hepatocyte-derived Huh-7 cells and primary rat hepatocytes, we found that mtAQP8 knockdown significantly downregulated de novo cholesterol synthesis as well as protein expressions of SREBP-2 and its target gene, a rate-limiting enzyme in cholesterol synthesis 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR). In contrast, adenovirus-mediated human AQP8 mitochondrial expression significantly increased de novo cholesterol synthesis and protein expressions of SREBP-2 and HMGCR. In mtAQP8-overexpressed hepatocytes, mitochondrial H 2 O 2 release was found to be increased; and a mitochondria-targeted antioxidant prevented the upregulation of mitochondrial H 2 O 2 release and that of cholesterol synthesis. Our results suggest that peroxiporin mtAQP8 plays a role in the SREBP-controlled hepatocyte cholesterogenesis, a finding that might be relevant to cholesterol-related metabolic disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Since cancer cells depend on de novo lipogenesis for energy supply, highly active membrane biosynthesis and signaling, enhanced fatty acid synthesis is a crucial characteristic of cancer cells. Hence, targeting lipogenic enzymes and signaling cascades is a very promising approach in developing innovative therapeutic agents for the fight against cancer. This review summarizes main aspects of altered fatty acid synthesis in cancer cells and emphasizes the power of chemical genetic approaches in identifying and analyzing novel anti-cancer drug candidates interfering with lipid metabolism., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Palatinose is a sucrose analog with a slower digestion rate than that of sucrose. For this reason, palatinose shows better effects on hepatic lipogenesis and cholesterol homeostasis compared with sucrose. We hypothesized that supplementation with palatinose instead of sucrose improves postprandial hyperglycemia and hyperinsulinemia in mice. Herein, we compared the digestion rates in vitro and observed physiological changes in vivo between sucrose- and palatinose-containing diets given to mice. Palatinose was hydrolyzed only by enzymes of the small intestine and was digested more slowly compared with sucrose in vitro. In mice, a diet containing palatinose resulted in significantly lower body weight gain and food efficiency rate values than those given a diet with sucrose. In this study, changes in serum biochemistry; hepatic fatty acid synthesis; cholesterol homeostasis; glucogenic, proinflammatory cytokines; and oxidative stress-related genes and proteins in the palatinose- and sucrose-fed mice were measured. Compared with the mice fed the sucrose diet, the palatinose diet resulted in lower serum glucose, insulin, and total cholesterol levels, as well as lower expression of several lipogenesis-related genes and proteins. Histological analysis of hepatic cells of palatinose-fed mice showed normal morphology. In conclusion, palatinose intake results in lower hepatic lipogenesis and better cholesterol homeostasis than the effects from sucrose., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Procyanidin B2, a naturally occurring phenolic compound, has been reported to exert multiple beneficial functions. However, the effect of procyanidin B2 on free fatty acids (FFAs)-induced hepatic steatosis remains obscure. The present study is therefore aimed to elucidate the protective effect of procyanidin B2 against hepatic steatosis and its underlying mechanism. Herein, we reported that procyanidin B2 attenuated FFAs-induced lipid accumulation and its associated oxidative stress by scavenging excessive ROS and superoxide anion radicals, blocking loss of mitochondrial membrane potential, restoring glutathione content, and increasing activity of antioxidant enzymes (GPx, SOD and CAT) in hepatocytes. Procyanidin B2 mechanistically promoted lipid degradation via modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathway. Molecular docking analysis indicated a possible ligand-binding position of procyanidin B2 with TFEB. In addition, administration of procyanidin B2 resulted in a significant reduction of hepatic fat accumulation in high-fat diet (HFD)-induced obese mice, and also ameliorated HFD-induced metabolic abnormalities, including hyperlipidemia and hyperglycemia. It was confirmed that procyanidin B2 prevented HFD-induced hepatic fat accumulation through down-regulating lipogenesis-related gene expressions (PPARγ, C/EBPα and SREBP-1c), inhibiting pro-inflammatory cytokines production (IL-6 and TNF-α) and increasing antioxidant enzymes activity (GPx, SOD and CAT). Moreover, hepatic fatty acids analysis indicated that procyanidin B2 caused a significant increase in the levels of palmitic acid, oleic acid and linoleic acid. Intriguingly, procyanidin B2 restored the decreased nuclear TFEB expression in HFD-induced liver steatosis and up-regulated its target genes involved in lysosomal pathway (Lamp1, Mcoln, Uvrag), which suggested a previously unrecognized mechanism of procyanidin B2 on ameliorating HFD-induced hepatic steatosis. Taken together, our results demonstrated that procyanidin B2 attenuated FFAs-induced hepatic steatosis through regulating TFEB-mediated lysosomal pathway and redox state, which had important implications that modulation of TFEB might be a potential therapeutic strategy for hepatic steatosis and procyanidin B2 could represent a promising novel agent in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD)., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hepatic stellate cells (HSCs) are universally acknowledged to play a core role in the pathogenesis of hepatic fibrosis. HSCs when activated are characterized by dramatic loss of intracellular lipid droplets. Accumulative evidence has suggested that recovery of lipid droplets could suppress HSC activation. However, the underlying molecular mechanisms still remain largely unclear. In this study, we found that the expression and activity of nuclear factor (erythroid-derived 2) - like 2 (Nrf2) were decreased in activated HSCs and negatively correlated with hepatic fibrosis severity in human liver specimens. Nrf2 overexpression, in contrast to Nrf2 deficiency, induced the accumulation of lipid droplets via decreasing the expression of lipolytic gene peroxisome proliferator-activated receptor alpha (PPARα) and increasing the expression of genes involved in lipogenesis and retinoic acid responsiveness, including CCAAT/enhancer-binding protein alpha, PPARγ, retinoid X receptor alpha, and retinoic acid receptor beta. Consequently, HSCs regained its lipocyte phenotype and expressed reduced alpha-smooth muscle actin and collagen type I. Consistently, disruption of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling by AG490 or Stattic could also induce lipocyte phenotype. Noticeably, Nrf2 overexpression by a genetic approach disrupted JAK2/STAT3 signaling and increased the expression of suppressor of cytokine signaling 3 (SOCS3) but not other protein inhibitors of activated STATs. Gain- or loss-of function of SOCS3 revealed that Nrf2 inhibited JAK2/STAT3 signaling via inducing SOCS3 expression. In conclusion, Nrf2 activation induced lipocyte phenotype in HSCs via enhancing SOCS3-dependent feedback inhibition on JAK2/STAT3 cascade. Nrf2 could be a target molecule for antifibrotic strategy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this study was to examine the temporal relationship between intramyocellular lipid (IMCL) content and the expression of genes associated with IMCL turnover, fat metabolism, and inflammation during recovery from an acute bout of resistance type exercise in old versus young men. Seven healthy young (23±2years, 77.2±2.9kg) and seven healthy older (72±1years, 79.3±4.9kg) males performed a single bout of resistance exercise involving 6 sets of 10 repetitions of leg press and 6 sets of 10 repetitions of leg extension at 75% one-repetition maximum (1-RM). Muscle biopsy samples were obtained before and 12, 24 and 48h after the completion of exercise and analysed for IMCL content and the expression of 48 genes. The subjects refrained from further heavy physical exercise and consumed a standardized diet for the entire experimental period. The IMCL content was ~2-fold higher at baseline and 12h post-exercise in old compared with young individuals. However, no differences between groups were apparent after 48h of recovery. There was higher expression of genes involved in fatty acid synthesis (FASN and PPARγ) during the first 24h of recovery. Differential responses to exercise were observed between groups for a number of genes indicating increased inflammatory response (IL6, IkBalpha, CREB1) and impaired fat metabolism and TCA cycle (LPL, ACAT1, SUCLG1) in older compared with younger individuals. A singe bout of resistance type exercise leads to molecular changes in skeletal muscle favouring reduced lipid oxidation, increased lipogenesis, and exaggerated inflammation during post-exercise recovery in the older compared with younger individuals, which may be indicative of a blunted response of IMCL turnover with ageing., (Copyright © 2017. Published by Elsevier Inc.)

Nonalcoholic fatty liver disease (NAFLD) is defined by a nonalcohol relevant pathological accumulation of fat in the liver. Previous studies have shown that sesamin exerts antioxidant effects and improves lipid metabolism of the fatty liver. In this study, we hypothesized that sesamin improves lipid homeostasis of Sprague-Dawley rats fed a high-fat diet (HFD) by regulating the expression of genes related to de novo lipogenesis and β-oxidation. We induced NAFLD in rats with HFD and examined the effect of sesamin in vivo. The results showed that HFD rats accumulated total cholesterol and triacylglycerols in the liver and developed inflammation, as evidenced by the elevation of interleukin-6 and tumor necrosis factor-α in the liver and serum. Sesamin attenuated the disease progression by improving the blood lipid profile in a dose-dependent manner. Sesamin reduced the serum levels of total cholesterol, triacylglycerols, low-density lipoprotein cholesterol, and free fatty acid, whereas it increased the level of high-density lipoprotein cholesterol. Meanwhile, sesamin increased the activities of hepatic glutathione peroxidase and superoxide dismutase while reducing the level of malonaldehyde and cytochrome P450 2E1. Furthermore, higher doses of sesamin reduced the expression of liver X receptor α and its downstream target genes, whereas it upregulated the peroxisome proliferator-activated receptor α-mediated signaling. These findings suggest that sesamin attenuates diet-induced dyslipidemia and inflammation of NAFLD in rats via mechanisms regulated by liver X receptor α and peroxisome proliferator-activated receptor α., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A high-fat diet may result in changes in hepatic clock gene expression, but potential mechanisms are not yet elucidated. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine protein kinase that is recognized as a key regulator of energy metabolism and certain clock genes. Therefore, we hypothesized that AMPK may be involved in the alteration of hepatic clock gene expression under a high-fat environment. This study aimed to examine the effects of timed high-fat evening diet on the activity of hepatic AMPK, clock genes, and lipogenic genes. Mice with hyperlipidemic fatty livers were induced by orally administering high-fat milk via gavage every evening (19:00-20:00) for 6 weeks. Results showed that timed high-fat diet in the evening not only decreased the hepatic AMPK protein expression and activity but also disturbed its circadian rhythm. Accordingly, the hepatic clock genes, including clock, brain-muscle-Arnt-like 1, cryptochrome 2, and period 2, exhibited prominent changes in their expression rhythms and/or amplitudes. The diurnal rhythms of the messenger RNA expression of peroxisome proliferator-activated receptorα, acetyl-CoA carboxylase 1α, and carnitine palmitoyltransferase 1 were also disrupted; the amplitude of peroxisome proliferator-activated receptorγcoactivator 1α was significantly decreased at 3 time points, and fatty liver was observed. These findings demonstrate that timed high-fat diet at night can change hepatic AMPK protein levels, activity, and circadian rhythm, which may subsequently alter the circadian expression of several hepatic clock genes and finally result in the disorder of hepatic lipogenic gene expression and the formation of fatty liver., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Although the expression of hepatic lipogenic genes is enhanced in insulin resistance, the underlying mechanism is unclear. To reveal the details, the aim of this study was to investigate whether the expression of hepatic lipogenic genes are mediated by epigenetic regulation and specific transcription factors in an insulin resistance model of rats., Methods: Using a rat model of insulin resistance (SHR/NDmc-cp), we investigated the relationship between hepatic expression of the lipogenic gene fatty-acid synthase (Fasn), binding of the transcription factor carbohydrate-responsive element-binding protein (ChREBP) to the Fasn gene, and histone modifications in the region of the Fasn gene by real-time reverse transcriptase polymerase chain reaction, immunoblotting, and chromatin immunoprecipitation assay., Results: Compared with control rats, Fasn mRNA expression and protein levels were higher in the livers of SHR/NDmc-cp rats, as were protein expression levels and Fasn binding of ChREBP and RNA polymerase II. Moreover, compared with the livers of control rats, levels of mono-methylated histone H3 lysine (K) 4 and acetylated histone H4 were higher in the promoter/enhancer region of the Fasn gene in the livers of SHR/NDmc-cp rats. Levels of trimethylated histone H3K4 and acetylated histone H3 were higher in the transcribed region., Conclusion: The results of this study indicate that expression of the Fasn gene in the livers of insulin-resistant rats is associated with increased H3K4 methylation, increased histone H3 acetylation, and increased H4 acetylation, and also, binding levels of ChREBP to promoter/enhancer region of Fasn gene is involved in the Fasn gene expression caused by hyperglycemia., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Previous work has demonstrated that elevated maternal lipid intake (particularly from dairy products) is associated with increased lipids and altered fatty acid profile in milk produced by healthy lactating women. To investigate our primary hypothesis that a maternal diet rich in full-fat dairy products would simultaneously increase milk lipid percent and expression of genes related to the uptake and/or de novo biosynthesis of milk lipids, we provided 15 lactating women with diets enriched in full-fat or nonfat dairy products for 14 days each in a randomized, crossover study with a 2-week washout period. Milk fat (%) was lower when women consumed the low-fat compared with the full-fat dairy diet (2.41% ± 0.31% vs 3.35% ± 0.28%, respectively; P < .05); concentrations of more than 20 fatty acids also differed. However, neither conservatively evaluated microarray data nor quantitative real-time polymerase chain reaction analysis uncovered any treatment effects on expression of genes related to lipid synthesis or uptake. These data suggest that alteration in gene expression in the lactating human mammary gland is likely not the primary mechanism by which consumption of a high-fat diet affects milk fat percent in healthy, lactating women., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Liver X receptor α (LXRα) plays an important role in the cholesterol metabolism process, and LXRα activation can reduce atherosclerosis. In the present study, using an LXRα-GAL4 luciferase reporter screening, we discovered IMB-170, a structural analog of quinazolinone, which showed potent LXRα agonistic activity. IMB-170 significantly activated LXRα, with an EC50 value of 0.27μM. Interestingly, IMB-170 not only increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), which are related to the reverse cholesterol transport (RCT) process, but also influenced the expression levels of other genes involved in the cholesterol metabolism pathway in many cell lines. Moreover, IMB-170 significantly reduced cellular lipid accumulation and increased cholesterol efflux from RAW264.7 and THP-1 macrophages. Interestingly, compared with TO901317, IMB-170 only slightly increased protein expression levels of lipogenesis-related genes in HepG2 cells, indicating that IMB-170 may have a lower lipogenesis side effect in vivo. These results suggest that IMB-170 showed the selective agonistic activity for LXRα. Moreover, compared with full LXR-agonists, IMB-170 possesses a differential ability to recruit coregulators. This suggests that IMB-170 has distinct interactions with the active sites in the LXRα ligand-binding domain. In summary, IMB-170 is a novel partial LXRα agonist without the classical lipogenesis side effects, which could be used as a potential anti-atherosclerotic leading compound in the future., (Copyright © 2014 Elsevier Inc. All rights reserved.)

High-fat diets (HFD) promote the development of both obesity and fatty liver disease through the up-regulation of hepatic lipogenesis. Insulin resistance, a hallmark of both conditions, causes dysfunctional fuel partitioning and increases in lipogenesis. Recent work has demonstrated that systemic insulin resistance occurs in as little as the first 72 hours of an HFD, suggesting the potential for hepatic disruption with HFD at this time point. The current study sought to determine differences in expression of lipogenic genes between sexes in 3-month-old male and female Long-Evans rats after 72 hours of a 40% HFD or a 17% fat (chow) diet. Owing to the response of estrogen on hepatic signaling, we hypothesized that a sexual dimorphic response would occur in the expression of lipogenic enzymes, inflammatory cytokines, apoptotic, and cell repair and remodeling genes. Both sexes consumed more energy when fed an HFD compared with their low fat-fed controls. However, only the males fed the HFD had a significant increase in body fat. Regardless of sex, HFD caused down-regulation of lipogenic and inflammatory genes. Interestingly, females fed an HFD had up-regulated expression of apoptotic and cell repair-related genes compared with the males. This may suggest that females are more responsive to the acute hepatic injury effects caused by HFDs. In summary, neither male nor female rats displayed disrupted hepatic metabolic pathways after 72 hours of the HFD treatment. In addition, female rats appear to have protection from increases in fat deposition, possibly due to increased caloric expenditure; male rats fed an HFD were less active, as demonstrated by distance traveled in their home cage., (© 2013.)

Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Nonalcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and insulin resistance. Furthermore, lipoic acid has been reported to have beneficial effects on mitochondrial function. In this study, we analyzed the potential protective effect of lipoic acid supplementation against the development of nonalcoholic steatosis associated with a long-term high-fat diet feeding and the potential mechanism of this effect. Wistar rats were fed on a standard diet (n=10), a high-fat diet (n=10) and a high-fat diet supplemented with lipoic acid (n=10). A group pair-fed to the latter group (n=6) was also included. Lipoic acid prevented hepatic triglyceride accumulation and liver damage in rats fed a high-fat diet (-68%±11.3% vs. obese group) through the modulation of genes involved in lipogenesis and mitochondrial β-oxidation and by improving insulin sensitivity. Moreover, this molecule showed an inhibitory action on electron transport chain complexes activities (P<.01-P<.001) and adenosine triphosphate synthesis (P<.05), and reduced significantly energy efficiency. By contrast, lipoic acid induced an increase in mitochondrial copy number and in Ucp2 gene expression (P<.001 vs. obese). In summary, this investigation demonstrated the ability of lipoic acid to prevent nonalcoholic steatosis induced by a high-fat intake. Finally, the novelty and importance of this study are the finding of how lipoic acid modulates some of the mitochondrial processes involved in energy homeostasis. The reduction in mitochondrial energy efficiency could also explain, at least in part, the beneficial effects of lipoic acid not only in fatty liver but also in preventing excessive body weight gain., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Phenolic compounds and flavonoids ameliorate bodyweight, blood glucose, and serum lipid profile. Since seabuckthorn (Hippophae rhamnoides L.) is known as a rich source of isoflavones and flavonoids, we hypothesized that ethanolic extract of seabuckthorn leaves (SL) may have anti-obesity and hypoglycemic effects. To investigate the effect of ethanolic extract of SL, 32 C57BL/6J mice were randomly divided into 4 dietary groups, containing 8 mice in each group: normal diet group; high-fat diet (HD) control group; high-fat diet with SL extract, 500 mg/kg body weight (BW) (SL1) group; and high-fat diet with SL extract, 1000 mg/kg BW (SL2) group. After 13 weeks, it was observed that oral administration of SL extract significantly reduced the energy intake; BW gain; epididymal fat pad weight; hepatic triglyceride, hepatic, and serum total cholesterol levels; and serum leptin levels in the SL groups compared to the HD group. However, differences in serum triglyceride and insulin levels in the SL groups were not significant in comparison to the HD group. The hepatic mRNA expression of peroxisome proliferator-activated receptor (PPAR) α and carnitine palmitoyltransferase 1 along with PPAR-γ were significantly increased in SL groups, whereas the level of acetyl-CoA carboxylase was significantly reduced in SL groups compared to HD group. Our results indicated that SL is effective in preventing BW gain and fat accumulation in the liver; it also reduced adipose tissue mass, hepatic lipid profile, and serum leptin level in the mouse. Together, these observations suggest that SL is a potential agent to study in the management of obesity and related disorders., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Cholesterol homeostasis is regulated by the liver X receptor (LXR) at the transcriptional level, but it remains unknown whether LXR can affect expression levels of intrahepatic lipolysis related gene. Recent evidence has demonstrated that fibroblast growth factor 21 (FGF21) regulates hepatic lipolysis and fatty acid utilization. In the present study, we examined the role of LXR in FGF21 gene expression associated with regulation of cross-talk signals between cholesterol and triglyceride metabolism in the liver. An in vivo cholesterol feeding test revealed that intake of excess cholesterol increased cholesterol catabolism related gene expression as well as fatty-acid biosynthesis related gene expression. Moreover, the accumulated cholesterol suppressed FGF21 and hormone-sensitive lipase (HSL) gene expression. After 15-day cholesterol feeding, hepatic triglyceride concentrations were negatively correlated with expression levels of the FGF21 and HSL genes in the liver. An LXR agonist (TO-901317) repressed the FGF21 gene expression in mouse primary hepatocytes and HepG2 cells. A promoter deletion study and electrophoretic mobility shift assay revealed that the human FGF21 promoter has at least one LXR response element located from -37 to -22 bp. In summary, LXR represses FGF21 gene expression at the transcription level and might suppress lipolysis and lipid utilization to protect the liver from excess accumulation of toxic cholesterol., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Stearoyl-CoA desaturase1 (SCD1) whole body deficiency protects mice from diet-induced obesity. However the specific mechanism of how SCD1 deficiency protects mice from obesity is not clear yet. To understand the tissue-specific role of SCD1 in energy homeostasis, we investigated the responses of adipocytes, hepatocytes and myotubes to SCD1 inhibition. 3T3-L1 adipocytes treated with a SCD1 inhibitor had decreased expression of lipogenic genes including fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and sterol-regulatory element binding protein 1c (SREBP1c) while the expression of fatty acid oxidative genes including carnitine palmitoyltransferase 1 (CPT1), uncoupling protein 2 (UCP2), and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α) remained unaltered. In mouse primary hepatocytes, treatment with the inhibitor reduced the expression of FAS, ACC, and SREBP1c but increased the expression of fatty acid oxidative genes including acyl-CoA oxidase (AOX), CPT1, and PGC1-α. In addition, inhibitor-treated C2C12 myotubes showed decrease in ACC and FAS expression and increase in expression of CPT1, AOX and PGC1-α. AMP-activated protein kinase (AMPK) is known to regulate cellular metabolism in response to available energy and AMPK activation is associated with enhancement of fatty acid oxidation and suppression of lipogenesis. In all tested cell models, AMPK phosphorylation was increased significantly when SCD1 was inhibited. Taken together, our results indicate that inhibition of SCD1 activity has beneficial lipid metabolic effects of decreased lipogenesis and/or increased fatty acid oxidation, which is at least in part due to an increase of AMPK activation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

This experiment was conducted to determine possible relationships between certain indices of lipid metabolism and specific gene expression in chickens fed graded levels of dietary crude protein. Male, broiler chickens (Gallus gallus) growing from 7 to 28days of age were fed diets containing 12 or 30% protein ad libitum. Both groups were then switched to the diets containing the opposite level of protein. Birds were sampled at 0, 6, 9, 12, 18 and 24h following the switch in protein levels. Measurements taken included in vitro lipogenesis (IVL), malic enzyme (ME), aspartate aminotransferase (AAT) and isocitrate dehydrogenase (NADP) (ICD) activities. In addition, ME, AAT, ICD, fatty acid synthase (FAS), and acetyl coenzyme carboxylase (ACC) gene expression rates were determined. IVL and ME activities were inversely related to dietary protein levels (12 to 30%) and to acute changes from 12 to 30%. In contrast, expression of ME, FAS and ACC genes was decreased by feeding a 30% protein diet (acute or chronic feeding). Results of the present study demonstrate a continued role for protein in the regulation of broiler metabolism. It should be pointed out; however, that metabolic regulation at the gene level only occurs when feeding very high or very low levels of dietary protein., (Published by Elsevier Inc.)

Recently, it has been demonstrated that fibroin and fibroin-derived peptides enhances insulin sensitivity and glucose metabolism in adipocytes. Here, we show that a synthetic hexapeptide Gly-Ala-Gly-Val-Gly-Tyr (GAGVGY) derived from repetitive amino acid sequence of fibroin improves glucose transport and exerts beneficial lipid metabolic effects in 3T3-L1 adipocytes. GAGVGY increases both basal and insulin-stimulated glucose uptake through enhancement of GLUT1 expression and PI 3-K-dependent GLUT4 translocation, respectively. GAGVGY treatment also led to a significant reduction in the expression of lipogenic genes including sterol regulatory element binding protein-1c (SREBP1c), peroxisome proliferator-activated receptor-γ (PPARγ), and fatty acid synthase (FAS) in mature 3T3-L1 adipocytes, which was corroborated with decreased lipid accumulation by GAGVGY treatment. Additionally, in cells undergoing differentiation, mRNA levels of adipogenic genes including PPARγ and CCAAT/enhancer binding protein α (C/EBPα), stearoyl-CoA desaturase 1 (SCD1), and FAS were suppressed by GAGVGY. Furthermore, GAGVGY increased AMP-activated protein kinase (AMPK) phosphorylation and adiponectin secretion in 3T3-L1 adipocytes. The latter effect was supported with evidence showing increased AMPK activation in C2C12 myocytes treated with 3T3-L1-adipocyte-conditioned medium. Together, our data suggest that GAGVGY has multiple beneficial effects on glucose and lipid metabolism, and would control hyperglycemia without the adverse effect of weight gain., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Isoliquiritigenin (ILQ), a flavonoid obtained from Glycyrrhizae species, has an antioxidant effect. This study investigated the potential of ILQ for inhibiting liver X receptor-α (LXRα)-mediated lipogenesis and steatosis in hepatocytes and its underlying molecular basis. Treatment with ILQ antagonized the ability of an LXRα agonist (T0901317) to activate sterol regulatory element binding protein-1c (SREBP-1c), thereby repressing transcription of fatty acid synthase, acetyl-CoA carboxylase, ATP-binding cassette transporter-A1, and stearoyl-CoA desaturase-1. ILQ treatment inhibited activating phosphorylation of JNK1 elicited by palmitate or TNFα. JNK1, but not JNK2, increased LXRα phosphorylation at serine residues, promoting LXRα activation. The ability of ILQ to inhibit JNK1 downstream of ASK1-MKK7 led to the repression of T0901317-inducible LXRα and SREBP-1c activation. In mice fed a high-fat diet, ILQ treatment inhibited hepatic steatosis, as shown by a decrease in fat accumulation and repression of lipogenic genes. The results of blood biochemistry and histopathology confirmed attenuation of high-fat diet-induced liver injury by ILQ. Moreover, ILQ inhibited oxidative stress, as indicated by decreases in thiobarbituric acid-reactive substance formation, iNOS and COX2 induction, and nitrotyrosinylation. Our results demonstrate that ILQ has the ability to repress LXRα-dependent hepatic steatosis through JNK1 inhibition and protect hepatocytes from oxidative injury inflicted by fat accumulation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. Several studies have shown that pharmacological concentrations of biotin reduce hypertriglyceridemia. The molecular mechanisms by which pharmacological concentrations of biotin affect lipid metabolism are largely unknown. The present study analyzed the effects of pharmacological doses of biotin on triglyceridemia, insulin sensitivity and on mRNA expression of various lipogenic genes. Three-week-old male BALB/cAnN Hsd mice were fed a biotin-control or a biotin-supplemented diet (1.76 or 97.7mg of free biotin/kg diet, respectively) over a period of eight weeks. Serum triglyceride concentrations, insulin and glucose tolerance and mRNA abundance of various lipogenic genes were investigated. The biotin-supplemented group showed 35% less serum triglycerides than control mice. In the liver, we found a significant (P<0.05) reduction of mRNA levels of SREBP1-c, glucose transporter-2, phosphofructokinase-1, pyruvate kinase, acetyl-CoA carboxylase and fatty acid synthase, while glucose-6-phosphate dehydrogenase expression increased. No changes in glucokinase, stearoyl-CoA desaturase-1, FoxO1 or PPAR-gamma expression were observed. In adipose tissue, we found a decreased expression of SREBP1c, glucose-6-phosphate deshydrogenase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase-1, phosphofructokinase-1 and PPAR-gamma, but no changes in FoxO1 expression. Moreover, the group fed a biotin-supplemented diet showed a significant decrease in adipose tissue weight. No differences in insulin sensitivity or serum insulin concentrations were observed between groups. Our results indicate that pharmacological concentrations of biotin decrease serum tryglyceride concentrations and lipogenic gene expression in liver and adipose tissues., (Copyright 2010 Elsevier B.V. All rights reserved.)

The precise mechanisms by which omega-3 fatty acids improve fat metabolism are not completely understood. This study was designed to determine the effects of eicosapentaenoic acid (EPA) ethyl ester administration on the expression levels of several muscle, liver and adipose tissue genes involved in lipogenesis and fatty acid oxidation pathways. Male Wistar rats fed a standard diet (control animals) or a high-fat diet were treated daily by oral gavage with EPA ethyl ester (1g/kg) for 5 weeks. The high-fat diet caused a very significant increase in plasma cholesterol (P<.01) levels, which was reverted by EPA (P<.001). A significant decrease in circulating triglyceride levels (P<.05) was also observed in EPA-treated groups. EPA administration induced a significant down-regulation in some lipogenic genes such as muscle acetyl CoA carboxylase beta (ACC beta) (P<.05) and liver fatty acid synthase (FAS) (P<.05). Furthermore, a decrease in glucokinase (GK) gene expression was observed in EPA-treated animals fed a control diet (P<.01), whereas a significant increase in GK mRNA levels was found in groups fed a high-fat diet. On the other hand, no alterations in genes involved in beta-oxidation, such acetyl CoA synthase 4 (ACS4), acetyl CoA synthase 5 (ACS5) or acetyl CoA oxidase (ACO), were found in EPA-treated groups. Surprisingly and opposite to the expectations, a very significant decrease in the expression levels of liver PPARalpha (P<.01) was observed after EPA treatment. These findings show the ability of EPA ethyl ester treatment to down-regulate some genes involved in fatty acid synthesis without affecting the transcriptional activation of beta-oxidation-related genes.

The purpose of these experiments were to determine possible relationships between certain indices of lipid metabolism and specific gene expression in chickens fed graded levels of dietary crude protein. Male, broiler chickens growing from 7 to 28 days of age were fed diets containing 12 or 30% protein ad libitum. Both groups were then switched on day 28 to the diets containing the opposite level of protein. Birds were killed on day 28 (basal values prior to the switch) and at 12, 18 and 24 h post switch. Measurements taken included in vitro lipogenesis, malic enzyme activity the expression of the genes for malic enzyme, fatty acid synthase and acetyl coenzyme carboxylase. In vitro lipogenesis and malic enzyme activity were inversely related to dietary protein levels (12 to 30%) and to acute changes from 12 to 30%. Malic enzyme, fatty acid synthase and acetyl coenzyme A carboxylase genes were constant over a dietary protein range of 12 to 21% as in previous experiments, but decreased by feeding a 30% protein diet in the present experiments (acute or chronic feeding). Results of the present study demonstrate a continued role for protein in the regulation of broiler metabolism. Metabolic regulation at the gene level only occurs when feeding very high levels of dietary protein.

Background: Hepatic de novo lipogenesis (DNL) is markedly stimulated in humans by low-fat diets enriched in simple sugars. However, the dietary responsiveness of the key enzyme controlling DNL in human adipose tissue, fatty acid synthase (FAS), is uncertain., Hypothesis: Adipose tissue mRNA for FAS is increased in lean and obese subjects when hepatic DNL is elevated by a eucaloric, low-fat, high-sugar diet., Design: Twelve lean and seven obese volunteers were given two eucaloric diets (10% vs. 30% fat; 75% vs. 55% carbohydrate; sugar/starch 60/40) each for 2 weeks by a random-order cross-over design. FAS mRNA in abdominal and gluteal adipose tissues was compared to hepatic DNL measured in serum by isotopic and nonisotopic methods. Adipose tissue mRNA for tumor necrosis factor-alpha and IL-6, which are inflammatory cytokines that modulate DNL, was also assayed., Results: The low-fat high-sugar diet induced a 4-fold increase in maximum hepatic DNL (P<.001) but only a 1.3-fold increase in adipose tissue FAS mRNA (P=.029) and no change in cytokine mRNA. There was a borderline significant positive correlation between changes in FAS mRNA and hepatic DNL (P=.039). Compared to lean subjects, obese subjects had lower levels of FAS mRNA and higher levels of cytokine mRNA (P<.001)., Conclusions: The results suggest that key elements of human adipose tissue DNL are less responsive to dietary carbohydrate than is hepatic DNL and may be regulated by diet-independent factors. Irrespective of diet, there is reduced expression of the FAS gene and increased expression of cytokine genes in adipose tissues of obese subjects.

Hubbard x Hubbard chickens (Gallus gallus) growing from 7 to 28 days of age were fed 12 or 30% protein diets and then switched to the diets containing the opposite level of protein. Birds were killed on days 28, 29, 30 and 31. Measurements taken included in vitro lipogenesis (IVL), malic enzyme (ME), isocitrate dehydrogenase (ICD) and aspartate aminotransferase (AAT) activities and the expression of the genes for ME, fatty acid synthase (FAS) and acetyl coenzyme carboxylase (ACC). Gene expression was determined with a combined RT-PCR using SYBR green as a fluorescent probe monitored in a real time mode. IVL and ME activity were inversely related to dietary protein levels (12 to 30%) and to acute changes in either level. In contrast, both ICD and AAT activities were increased by any increase in dietary protein. Lipogenic gene expression was inversely related to protein level, whether fed on an acute or chronic basis. It appears that real time RT-PCR is an acceptable method of estimating gene expression in birds. In addition, further work will focus on primer sizes that might further optimize RT-PCR as an instrument for studying the regulation of avian lipid metabolism. Results of the present study demonstrate a continued role for protein in the regulation of broiler metabolism. However, it should be pointed out that metabolic regulation at the gene level only occurs when feeding very high levels of dietary protein.