Terminalia paniculata bark extract attenuates non-alcoholic fatty liver via down regulation of fatty acid synthase in high fat diet-fed obese rats

Background/Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2) is involved in high fat diet (HFD)-induced NAFLD and possible molecular mechanisms. Methods: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively. Western blotting was applied to detect the protein expressions of lipid synthesis-related enzymes and the phosphorylated level of IRS-1, Akt and mTOR. Results: ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT), aspartate transaminase (AST) and insulin. Knockdown of ClC-2 in liver attenuated HFD-induced weight gain, obesity, hepatocellular ballooning, and liver lipid accumulation and fibrosis, accompanied by reduced plasma free fatty acid (FFA), triglyceride (TG), total cholesterol (TC), ALT, AST, glucose and insulin levels and homeostasis model of insulin resistance (HOMA-IR) value. Moreover, HFD-treated mice lacking ClC-2 showed inhibited hepatic lipid accumulation via regulating lipid metabolism through decreasing sterol regulatory element binding protein (SREBP)-1c expression and its downstream targeting enzymes such as fatty acid synthase (FAS), HMG-CoA reductase (HMGCR) and acetyl-Coenzyme A carboxylase (ACCα). In addition, in vivo and in vitro results demonstrated that ClC-2 downregulation in HFD-treated mice or HepG2 cells increased the sensitivity to insulin via activation of IRS-1/Akt/mTOR signaling pathway. Conclusion: Our present study reveals a critical role of ClC-2 in regulating metabolic diseases. Mice lacking ClC-2 are associated with a remarkably beneficial metabolic phenotype, suggesting that decreasing ClC-2 may be an attractive therapeutic strategy for the treatment of NAFLD.

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Fatty acid composition in serum correlates with that in the liver and non-alcoholic fatty liver disease activity scores in mice fed a high-fat diet

Environmental Toxicology and Pharmacology ◽

10.1016/j.etap.2016.04.009 ◽

2016 ◽

Vol 44 ◽

pp. 140-150 ◽

Cited By ~ 19

Author(s):

Xing-he Wang ◽

Chun-yan Li ◽

Ishfaq Muhammad ◽

Xiu-ying Zhang

Keyword(s):

Fatty Acid Composition ◽

Fatty Acid ◽

Liver Disease ◽

Fatty Liver ◽

Disease Activity ◽

High Fat Diet ◽

Fatty Liver Disease ◽

High Fat ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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A high‐fat diet leads to the progression of non‐alcoholic fatty liver disease in obese rats

The FASEB Journal ◽

10.1096/fj.04-2291fje ◽

2004 ◽

Vol 19 (1) ◽

pp. 136-138 ◽

Cited By ~ 190

Author(s):

Michal Carmiel-Haggai ◽

Arthur I. Cederbaum ◽

Natalia Nieto

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

High Fat ◽

Alcoholic Fatty Liver ◽

Obese Rats ◽

Alcoholic Fatty Liver Disease

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Sodium fluorocitrate having inhibitory effect on fatty acid uptake ameliorates high fat diet-induced non-alcoholic fatty liver disease in C57BL/6J mice

Scientific Reports ◽

10.1038/s41598-019-54476-5 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Seung A. Hong ◽

Ik-Rak Jung ◽

Sung-E. Choi ◽

Yoonjung Hwang ◽

Soo-Jin Lee ◽

...

Keyword(s):

Fatty Acid ◽

Liver Disease ◽

Fatty Liver ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

High Fat ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) is excessive fat build-up in the liver without alcohol consumption and includes hepatic inflammation and damage. Excessive influx of fatty acids to liver from circulation is thought to be a pathogenic cause for the development of NAFLD. Thus, inhibition of fatty acid intake into hepatocyte would be a maneuver for protection from high fat diet (HFD)-induced NAFLD. This study was initiated to determine whether sodium fluorocitrate (SFC) as a fatty acid uptake inhibitor could prevent palmitate-induced lipotoxicity in hepatocytes and protect the mice from HFD-induced NAFLD. SFC significantly inhibited the cellular uptake of palmitate in HepG2 hepatocytes, and thus prevented palmitate-induced fat accumulation and death in these cells. Single treatment with SFC reduced fasting-induced hepatic steatosis in C57BL/6J mice. Concurrent treatment with SFC for 15 weeks in HFD-fed C57BL/6J mice prevented HFD-induced fat accumulation and stress/inflammatory signal activation in the liver. SFC restored HFD-induced increased levels of serum alanine aminotransferase and aspartate aminotransferases as hepatic injury markers in these mice. SFC treatment also improved HFD-induced hepatic insulin resistance, and thus ameliorated HFD-induced hyperglycemia. In conclusion, inhibition of fatty acid mobilization into liver through SFC treatment can be a strategy to protect from HFD-induced NAFLD.

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Acer tegmentosum Maxim Inhibits Adipogenesis in 3t3-l1 Adipocytes and Attenuates Lipid Accumulation in Obese Rats Fed a High-Fat Diet

Nutrients ◽

10.3390/nu12123753 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3753

Author(s):

Hang-Hee Cho ◽

Soo-Jung Lee ◽

Sung-Ho Kim ◽

Sun-Hee Jang ◽

Chungkil Won ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Fatty Acid ◽

Lipid Accumulation ◽

High Fat Diet ◽

Fatty Acid Synthase ◽

Binding Protein ◽

High Fat ◽

Fatty Acid Binding ◽

Obese Rats

We investigated the effect of Acer tegmentosum Maxim (ATM) on adipocyte differentiation in 3T3-L1 cells and anti-obesity properties in obese rats fed a high-fat diet (HFD). Cellular lipid content in DMI (dexamethasone, 3–isobutyl–1–methylxanthine, and insulin mixture)-treated cells increased, while ATM treatment caused a significant reduction in lipid accumulation in differentiated 3T3-L1 cells. ATM (60 ug/mL) caused inhibition of adipogenesis via down-regulation of the CCAAT/enhancer binding protein β (C/EBPβ) (48%), C/EBPα (66%), and peroxisome proliferator-activated receptor γ (PPARγ) (64%) expressions in 3T3-L1 cells. Moreover, ATM induced a decrease in the expressions of adipocyte-specific genes, such as adipocyte fatty acid-binding protein-2 (aP2), fatty acid synthase (FAS), and lipoprotein lipase (LPL). Protein kinase B (Akt) and glycogen synthase kinase 3β (GSK3β) phosphorylation was also decreased by ATM treatment of 3T3-L1 adipocytes. We investigated the anti-obesity effects of ATM on HFD-induced obese rats. Rats fed with an HFD demonstrated elevations in body weight gain, while the administration of ATM reversed body weight (BW) gains and adipose tissue weights in rats fed an HFD. ATM supplementation caused a decrease in the circulating triglyceride and total cholesterol levels and led to inhibition of lipid accumulation in the adipose tissues in HFD-induced obese rats. Epididymal fat exhibited significantly larger adipocytes in the HFD group than it did in the ATM-treated group. These results demonstrate that ATM administration caused a reduction in adiposity via attenuation in adipose tissue mass and adipocyte size.

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