Free fatty acids induce the demethylation of fructose 1,6-biphosphatase 2 gene promoter and potentiate its expression in hepatocytes

Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by the excess accumulation of fat in the hepatocytes. It is commonly associated with severe obesity and inflammation. Free fatty acids (FFAs) are the key to regulate lipid metabolism and immune response in hepatocyte cells. This study examined the effects of AEN (alcohol extract of nutmeg, the seed of Myristica fragrans Houtt.) on the inhibition of lipid synthesis and inflammation in vitro and in vivo and on high-fat diet-induced obesity in NAFLD mice. Our results showed that AEN treatment could downregulate the expression of lipid synthesis-related genes fatty acid synthase (FASN) and sterol regulatory element-binding protein 1c (SREBP-1c) and lower the lipid content of cells. AEN also inhibited FFAs-mediated inflammation-related cytokines interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) expression in cells. In a mouse model, AEN reduced the bodyweight of obese mice and improved NAFLD without affecting food intake. Further analysis revealed that AEN significantly reduced inflammation level, cholesterol and lipid accumulation, blood glucose, and other liver function indexes in mice fed with a high-fat diet. In conclusion, AEN inhibited the aggravation of obesity and inflammation by downregulating lipid-gene expression in the liver to ameliorate NAFLD.

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Mogroside V Protects against Hepatic Steatosis in Mice on a High-Fat Diet and LO2 Cells Treated with Free Fatty Acids via AMPK Activation

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7826874 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Linghuan Li ◽

Wanfang Zheng ◽

Can Wang ◽

Jiameng Qi ◽

Hanbing Li

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Lipid Metabolism ◽

Free Fatty Acids ◽

Mrna Expression ◽

Hepatic Steatosis ◽

High Fat Diet ◽

De Novo ◽

Acid Oxidation ◽

High Fat

Previous studies presented various beneficial effects of mogrosides extract from Siraitia grosvenorii, which has been included in the list of Medicine Food Homology Species in China. Mogroside V (MV) is one of the main ingredients in mogrosides extract; however, whether and how MV improves impaired lipid metabolism in the liver remains to be elucidated. Herein, we investigated the therapeutic effects of mogroside V upon hepatic steatosis in vivo and in vitro and explored the underlying mechanisms. The results showed that MV significantly ameliorated hepatic steatosis in high-fat diet- (HFD-) fed mice. Furthermore, the increased protein expression of PPAR-γ, SREBP-1, and FASN and mRNA expression of pparg, srebp1, scd1, and fasn in the liver in HFD-fed mice, which contribute to de novo lipogenesis, were dose-dependently reversed by MV treatment. Meanwhile, MV counteracted the suppressed expression of PPAR-α and CPT-1A and mRNA expression of atgl, hsl, ppara, and cpt1a, thus increasing lipolysis and fatty acid oxidation. In addition, in free fatty acids- (FFAs-) incubated LO2 cells MV downregulated de novo lipogenesis and upregulated lipolysis and fatty acid oxidation, thereby attenuating lipid accumulation, which was significantly abrogated by treatment with Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Taken together, these results suggested that MV exerted a pronounced effect upon improving hepatic steatosis through regulating the disequilibrium of lipid metabolism in the liver via an AMPK-dependent pathway, providing a potential lead compound candidate for preventing nonalcoholic fatty liver disease.

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Sex Differences in Gut Microbiome in High-Fat-Diet Fed Rats

10.21203/rs.3.rs-98831/v1 ◽

2020 ◽

Author(s):

Ying Shi ◽

Fangzhi Yue ◽

Lin Xing ◽

Shanyu Wu ◽

Lin Wei ◽

...

Keyword(s):

Fatty Acids ◽

Body Weight ◽

Sex Differences ◽

Gut Microbiota ◽

High Fat Diet ◽

Metabolic Diseases ◽

Normal Diet ◽

Female Rats ◽

Male Rats ◽

High Fat

Abstract Background: Sex differences in obesity and related metabolic diseases are well recognized, however, the mechanism has not been elucidated. Gut microbiota and its metabolites may play a vital role in the development of obesity and metabolic diseases. The aim of the present study was to investigate sex differences in gut microbiota and its metabolites in a high-fat-diet (HFD) obesity rats and identify microbiota genera potentially contributing to such differences in obesity and non-alcoholic fatty liver disease (NAFLD) susceptibility.Methods: Sprague–Dawley rats were divided into four groups (eight animals per group): (1) male rats on a normal diet (MND), (2) male rats on HFD (MHFD), (3) female rats on a normal diet (FND), and (4) female rats on HFD (FHFD). Body weight, liver pathology, gut microbiota and short/medium chain fatty acids in colon contents were compared between different sexes.Results: HFD induced more body weight gain and fat storage in female rats, however, lower hepatic steatosis in FHFD than in MHFD rats was observed. When considering gut microbiota composition, FHFD rats had lower microbiome diversity than MHFD. A significant increase of Firmicutes phylum, along with Bilophila and Blautia genus was detected in MHFD rats, as compared with FHFD, which showed increased relative abundance of Murimonas. Moreover, propionic and lauric acid levels were higher in FHFD than those in MHFD rats. Conclusions: HFD induced sex-related alterations in gut microbiome and fatty acids. Furthermore, the genus Bilophila, Blautia and Murimonas might contribute to sex differences observed in obesity and NAFLD susceptibility.

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Free Fatty Acids Induce Lhb mRNA but Suppress Fshb mRNA in Pituitary LβT2 Gonadotropes and Diet-Induced Obesity Reduces FSH Levels in Male Mice and Disrupts the Proestrous LH/FSH Surge in Female Mice

Endocrinology ◽

10.1210/en.2012-2218 ◽

2013 ◽

Vol 154 (6) ◽

pp. 2188-2199 ◽

Cited By ~ 26

Author(s):

Shweta Sharma ◽

Hidetaka Morinaga ◽

Vicky Hwang ◽

WuQiang Fan ◽

Marina O. Fernandez ◽

...

Keyword(s):

Fatty Acids ◽

Free Fatty Acids ◽

Mrna Expression ◽

High Fat Diet ◽

Mapk Signaling ◽

Seminiferous Tubules ◽

Corpora Lutea ◽

Toll Like Receptor ◽

High Fat ◽

Female Mice

Abstract Female obesity is associated with insulin resistance, hyperandrogenemia, and reproductive dysfunction. We hypothesized that elevated free fatty acids (FFAs) might directly modulate pituitary gonadotropin production. FFAs caused a time- and dose-dependent increase in phosphorylation of the MAPKs p38MAPK, c-Jun N-terminal kinase (JNK)-1/2, and ERK1/2 in LβT2 gonadotrope cells. Furthermore, FFAs up-regulated Lhb mRNA expression acutely, an effect that was blocked by JNK inhibition, but suppressed Fshb mRNA expression, an effect that was independent of MAPK signaling. FFAs enhanced the activation of the MAPKs in the presence of GnRH, although the cotreatment did not alter Lhb induction but did eliminate the GnRH induction of Fshb. FFAs also suppressed activin-induced Fshb expression. Knockdown experiments showed that the FFA effect on the inflammatory kinases p38MAPK and JNK and on Lhb, but not Fshb, mRNA expression is mediated via toll-like receptor-2 and toll-like receptor-4 and was mimicked by lipopolysaccharide stimulation. In vivo, male C57BL/6 mice on a high-fat diet showed reduced FSH levels consistent with the suppression of Fshb seen in vitro. Histological analysis of the testes showed an increased number of abnormal seminiferous tubules. Female mice on a high-fat diet lacked the expected proestrus LH and FSH surge and exhibited an increase in the number of days at estrus and a reduced number of days at proestrus, and ovaries had significantly fewer corpora lutea. Taken together, our findings suggest that lipid excess can lead to reproductive defects in both male and female mice.

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