Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (<i>db/db</i>) Mice via Stimulating ATG7-Dependent Autophagy

Xiao, Yuzhong; Liu, Hao; Yu, Junjie; Zhao, Zilong; Xiao, Fei; Xia, Tingting; Wang, Chunxia; Li, Kai; Deng, Jiali; Guo, Yinlong; Chen, Shanghai; Chen, Yan; Guo, Feifan

doi:10.2337/db15-1024

Cited by 43 publications

(36 citation statements)

References 52 publications

(74 reference statements)

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“…In the present study, we found that miR-30c-5p was significantly decreased in liver of leptin receptor deficient (db/db) mice, a classic animal model for liver steatosis [5]. And strikingly, exogenous miR-30c-5p delivered by recombinant adeno-associated virus (rAAV) markedly ameliorated abnormal triglyceride accumulation and liver steatosis in db/db mice, suggesting a new therapeutic strategy against NAFLD.…”

Section: Introductionmentioning

confidence: 82%

“…NAFLD is composed of a series of pathological changes in liver: 1) The initial stage is hepatic steatosis, characterized by the excess deposition of triglyceride and/or cholesterol in liver; 2) Abnormal hepatic lipid accumulation results from augmented de novo lipogenesis, and/or decreased β-oxidation; 3) If uncontrolled, hepatic steatosis can progress to cirrhosis, end-stage liver failure and hepatocellular carcinoma [4, 5]. Currently, no drug is licensed for the treatment of NAFLD [3, 6], and thus it is important to understand the mechanisms underlying NAFLD and develop new intervention strategies.…”

Section: Introductionmentioning

confidence: 99%

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MiR-30c-5p ameliorates hepatic steatosis in leptin receptor-deficient (db/db) mice via down-regulating FASN

Fan

Nie

et al. 2017

Oncotarget

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Approximately 15–40% of the general adult population suffers from non-alcoholic fatty liver disease (NAFLD) worldwide. However, no drug is currently licensed for its treatment. In this study, we observed a significant reduction of miR-30c-5p in the liver of leptin receptor-deficient (db/db) mice. Remarkably, recombinant adeno-associated virus (rAAV)-mediated delivery of miR-30c-5p was sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice. Through computational prediction, KEGG analysis and Ago2 co-immunoprecipitation, we identified that miR-30c-5p directly targeted fatty acid synthase, a key enzyme in fatty acid biosynthesis. Moreover, down-regulation of FASN by siRNA attenuated some key features of NAFLD, including decreased triglyceride accumulate and lipid deposition. Our findings reveal a new role of miR-30c-5p in counterbalancing fatty acid biosynthesis, which is sufficient to attenuate triglyceride accumulation and hepatic steatosis in db/db mice.

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Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

MiR-30c-5p ameliorates hepatic steatosis in leptin receptor-deficient (db/db) mice via down-regulating FASN

Fan

Nie

et al. 2017

Oncotarget

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“…Biochemical Analysis-Hepatic and cellular lipids were extracted with chloroform/methanol (2:1), as described previously (51,52). TG, TC, FFAs, ALT, and AST were determined using a TG kit (BHKT Clinical Reagents, Beijing, China), a TC kit (SSUF-C, Shanghai, China), an FFA kit (Wako Pure Chemical Industries, Osaka, Japan), and an AST or ALT kit (ShenSuoYouFu, Shanghai, China), respectively.…”

Section: Methodsmentioning

confidence: 99%

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Li¹,

Xiao²,

et al. 2016

Journal of Biological Chemistry

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Although numerous biological functions of the activating transcription factor 4 (ATF4) have been identified, a direct effect of ATF4 on alcoholic liver steatosis has not been described previously. The aim of our current study is to investigate the role of ATF4 in alcoholic liver steatosis and elucidate the underlying mechanisms. Here, we showed that the expression of ATF4 is induced by ethanol in hepatocytes in vitro and in vivo, and liverspecific ATF4 knock-out mice are resistant to ethanol-induced liver steatosis, associated with stimulated hepatic AMP-activated protein kinase (AMPK) activity. Furthermore, adenovirus-mediated AMPK knockdown significantly reversed the suppressive effects of ATF4 deficiency on ethanol-induced liver steatosis in mice. In addition, ethanol-fed ATF4 knock-out mice exhibit AMPK-dependent inhibition of fatty acid synthase and stimulation of carnitine palmitoyltransferase 1 (CPT1) in the liver. Moreover, hepatic Tribbles homolog 3 (TRB3) expression was stimulated by ethanol in an ATF4-dependent manner, and adenovirus-mediated TRB3 knockdown blocked ATF4-dependent ethanol-induced AMPK inhibition and triglyceride accumulation in AML-12 cells. Finally, TRB3 directly interacted with AMPK to suppress its phosphorylation. Taken together, these results identify the ATF4-TRB3-AMPK axis as a novel pathway responsible for ethanol-induced liver steatosis.People consuming excessive amounts of alcohol for prolonged periods suffer from alcoholic liver disease, which encompasses fatty liver, hepatic inflammation and necrosis, progressive fibrosis, and hepatocellular carcinoma (1). Alcoholic fatty liver is the early stage of alcoholic liver disease, characterized by increased accumulation of fat in the liver, which is usually caused by increased free fatty acid (FFA) 4 uptake, augmented de novo lipogenesis, decreased ␤-oxidation, and/or impaired triglyceride (TG) export (2). Studies have identified some important regulators for ethanol-induced liver steatosis, including sirtuin 1 (SIRT1) (3), sterol regulatory element-binding protein 1 (SREBP-1) (4), peroxisome proliferator-activated receptor ␥ coactivator 1-␣ (PGC-1␣) (5), and 5Ј-adenosine monophosphate-activated protein kinase (AMPK) (6 -8).Among them, AMPK is one of the most important regulators (6 -8). AMPK is a heterotrimeric complex consisting of a catalytic ␣ subunit and two regulatory ␤/␥ subunits. It acts as a key metabolic "switch" by phosphorylating target enzymes involved in lipid metabolism, such as acetyl-CoA carboxylase (ACC) (9). Malonyl-CoA, the product of ACC, is both a precursor for fatty acid biosynthesis and a potent inhibitor of ␤-oxidation at the step regulated by carnitine palmitoyltransferase I (10). AMPK activity is suppressed under ethanol exposure (6) and activation of AMPK by its activator (5-aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside) or metformin prevents ethanol-induced liver steatosis (11, 12). However, the molecular mechanisms underlying ethanol suppression of AMPK activity remain largely unknown. Activating...

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“…Although some studies showed the lipogenic role of autophagy, most experiments supported autophagy as a lipolytic mechanism (6). Reduced autophagic function promotes the initial development of hepatic steatosis and progression of steatosis to liver injury, and agents to augment hepatic autophagy may have therapeutic potential in nonalcoholic steatohepatitis (8)(9)(10).…”

mentioning

confidence: 99%

FNDC5 Alleviates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice

et al. 2016

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Fibronectin type III domain-containing 5 (FNDC5) protein induces browning of subcutaneous fat and mediates the beneficial effects of exercise on metabolism. However, whether FNDC5 is associated with hepatic steatosis, autophagy, fatty acid oxidation (FAO), and lipogenesis remains unknown. Herein, we show the roles and mechanisms of FNDC5 in hepatic steatosis, autophagy, and lipid metabolism. Fasted FNDC5 mice exhibited severe steatosis, reduced autophagy, and FAO, and enhanced lipogenesis in the liver compared with wild-type mice. Energy deprivation-induced autophagy, FAO, and AMPK activity were attenuated in FNDC5 hepatocytes, which were restored by activating AMPK with 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). Inhibition of mammalian target of rapamycin (mTOR) complex 1 with rapamycin enhanced autophagy and FAO and attenuated lipogenesis and steatosis in FNDC5 livers. FNDC5 deficiency exacerbated hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis, and lipid accumulation in obese mice. Exogenous FNDC5 stimulated autophagy and FAO gene expression in hepatocytes and repaired the attenuated autophagy and palmitate-induced steatosis in FNDC5 hepatocytes. FNDC5 overexpression prevented hyperlipemia, hepatic FAO and autophagy impairment, hepatic lipogenesis, and lipid accumulation in obese mice. These results indicate that FNDC5 deficiency impairs autophagy and FAO and enhances lipogenesis via the AMPK/mTOR pathway. FNDC5 deficiency aggravates whereas FNDC5 overexpression prevents the HFD-induced hyperlipemia, hepatic lipid accumulation, and impaired FAO and autophagy in the liver.

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Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy

Cited by 43 publications

References 52 publications

MiR-30c-5p ameliorates hepatic steatosis in leptin receptor-deficient (db/db) mice via down-regulating FASN

MiR-30c-5p ameliorates hepatic steatosis in leptin receptor-deficient (db/db) mice via down-regulating FASN

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

FNDC5 Alleviates Hepatosteatosis by Restoring AMPK/mTOR-Mediated Autophagy, Fatty Acid Oxidation, and Lipogenesis in Mice

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