scholarly journals Fatty Acid Synthase Inhibitor Platensimycin Intervenes the Development of Nonalcoholic-Fatty Liver Disease in a Mouse Model

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 5
Author(s):  
Meng Su ◽  
Danfeng Cao ◽  
Zhe Wang ◽  
Yanwen Duan ◽  
Yong Huang
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Mouse Model ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Fatty Acid Synthase ◽  
Western Diet ◽  
World Population ◽  
Mrna Levels ◽  
Alcoholic Fatty Liver

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting about 25% of world population, while there are still no approved targeted therapies. Although platensimycin (PTM) was first discovered to be a broad-spectrum antibiotic, it was also effective against type II diabetes in animal models due to its ability to inhibit both bacterial and mammalian fatty acid synthases (FASN). Herein, we report the pharmacological effect and potential mode of action of PTM against NAFLD in a Western diet/CCI4-induced mouse model and a free fatty acids (FFAs)-induced HepG2 cell model. The proper dose of PTM and its liposome-based nano-formulations not only significantly attenuated the Western diet-induced weight gain and the levels of plasma total triglycerides and glucose, but reduced liver steatosis in mice according to histological analyses. Western blotting analysis showed a reduced protein level of FASN in the mouse liver, suggesting that PTM intervened in the development of NAFLD through FASN inhibition. PTM reduced both the protein and mRNA levels of FASN in FFAs-induced HepG2 cells, as well as the expression of several key proteins in lipogenesis, including sterol regulatory element binding protein-1, acetyl-CoA carboxylase, and stearoyl-CoA desaturase. The expression of lipid oxidation-related genes, including peroxisome proliferator activated receptor α and acyl-CoA oxidase 1, was significantly elevated. In conclusion, our study supports the reposition of PTM to intervene in NAFLD progression, since it could effectively inhibit de novo lipogenesis.

scholarly journals Arazyme Suppresses Hepatic Steatosis and Steatohepatitis in Diet-Induced Non-Alcoholic Fatty Liver Disease-Like Mouse Model

2019 ◽  
Vol 20 (9) ◽  
pp. 2325 ◽  
Author(s):  
Hua Li ◽  
Wonbeak Yoo ◽  
Hye-Mi Park ◽  
Soo-Youn Lim ◽  
Dong-Ha Shin ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Diet Group ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Arazyme, a metalloprotease from the spider Nephila clavata, exerts hepatoprotective activity in CCL4-induced acute hepatic injury. This study investigated the hepatoprotective effects in high-fat diet (HFD)-induced non-alcoholic fatty liver disease-like C57BL/6J mice. The mice were randomly divided into four groups (n = 10/group): the normal diet group, the HFD group, the arazyme group (HFD with 0.025% arazyme), and the milk thistle (MT) group (HFD with 0.1% MT). Dietary supplementation of arazyme for 13 weeks significantly lowered plasma triglyceride (TG) and non-esterified fatty acid levels. Suppression of HFD-induced hepatic steatosis in the arazyme group was caused by the reduced hepatic TG and total cholesterol (TC) contents. Arazyme supplementation decreased hepatic lipogenesis-related gene expression, sterol regulatory element-binding transcription protein 1 (Srebf1), fatty acid synthase (Fas), acetyl-CoA carboxylase 1 (Acc1), stearoyl-CoA desaturase-1 (Scd1), Scd2, glycerol-3-phosphate acyltransferase (Gpam), diacylglycerol O-acyltransferase 1 (Dgat1), and Dgat2. Arazyme directly reduced palmitic acid (PA)-induced TG accumulation in HepG2 cells. Arazyme suppressed macrophage infiltration and tumor necrosis factor α (Tnfa), interleukin-1β (Il1b), and chemokine-ligand-2 (Ccl2) expression in the liver, and inhibited secretion of TNFα and expression of inflammatory mediators, Tnfa, Il1b, Ccl2, Ccl3, Ccl4, and Ccl5, in PA-induced RAW264.7 cells. Arazyme effectively protected hepatic steatosis and steatohepatitis by inhibiting SREBP-1-mediated lipid accumulation and macrophage-mediated inflammation.

Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease

2014 ◽  
Vol 306 (4) ◽  
pp. G320-G327 ◽  
Author(s):  
Shobha H. Ganji ◽  
Gary D. Kukes ◽  
Nils Lambrecht ◽  
Moti L. Kashyap ◽  
Vaijinath S. Kamanna
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Fatty Acid Synthase ◽  
Liver Fat ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.

scholarly journals The DNA damage checkpoint protein ATM promotes hepatocellular apoptosis and fibrosis in a mouse model of non-alcoholic fatty liver disease

Cell Cycle ◽  
2012 ◽  
Vol 11 (10) ◽  
pp. 1918-1928 ◽  
Author(s):  
Erin K. Daugherity ◽  
Gabriel Balmus ◽  
Ahmed Al Saei ◽  
Elizabeth S. Moore ◽  
Delbert Abi Abdallah ◽  
...  
Keyword(s):  
Dna Damage ◽  
Liver Disease ◽  
Mouse Model ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Dna Damage Checkpoint ◽  
Alcoholic Fatty Liver ◽  
Checkpoint Protein ◽  
Hepatocellular Apoptosis ◽  
Alcoholic Fatty Liver Disease

scholarly journals Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease

2014 ◽  
Vol 279 (3) ◽  
pp. 380-390 ◽  
Author(s):  
Banrida Wahlang ◽  
Ming Song ◽  
Juliane I. Beier ◽  
K. Cameron Falkner ◽  
Laila Al-Eryani ◽  
...  
Keyword(s):  
Liver Disease ◽  
Mouse Model ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Alcoholic Fatty Liver Disease

scholarly journals Diospyros kaki and Citrus unshiu Mixture Improves Disorders of Lipid Metabolism in Nonalcoholic Fatty Liver Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Mi-Rae Shin ◽  
Sung Ho Shin ◽  
Seong-Soo Roh
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Fatty Acid Synthase ◽  
Diospyros Kaki ◽  
Citrus Unshiu ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) has been a major cause of a chronic liver disease over recent decades and increasing worldwide in parallel with the remarkable growth of obesity. In the present study, we investigate the ameliorative effects of PCM, a combination of Diospyros kaki fruit and Citrus unshiu peel mixture, on high-fat diet- (HFD-) induced NAFLD and clarify the potential mechanisms. PCM in HFD-fed mice was orally administered at a dose of 50 or 100 mg/kg subsequently for 2 months. Thereafter, lipid metabolism parameters and fat synthesis-related genes in the mouse liver were evaluated. Subsequently, body weight changes, liver weight, serum liver function and lipid profiles, and liver pathology were examined, and the relative levels of fatty acid synthesis and β-oxidation gene expression were evaluated by western blot. Serum AST, ALT, and TG levels in the HFD control mice were significantly higher than those of normal mice. Compared with HFD control mice, PCM supplementation increased phosphorylation of AMP-activated protein kinase (AMPK). Peroxisome proliferator-activated receptor (PPAR) α was significantly increased by PCM administration. Continuously, the activation of PPARα significantly elevated carnitine palmitoyltransferase 1 (CPT-1), a key enzyme in fatty acid β-oxidation, and mitochondrial uncoupling protein 2 (UCP-2), thermogenic regulatory genes, in PCM-treated mice compared with those of HFD control mice. Moreover, PCM inhibits lipogenesis and cholesterol synthesis via suppression of sterol regulatory element binding protein-1 (SREBP-1) and SREBP-2 and its target genes such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Taken together, these effects were mediated through activation of AMPK. In the conclusion, PCM improved liver damage in HFD-fed mice and attenuated NAFLD by the activation of PPARα and the inhibition of SREBPs expression via AMPK-dependent pathways.

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