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Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP12 protects against hepatic steatosis and inflammation in L02 cells after palmitic acid/oleic acid treatment. We demonstrate that hepatocyte specific DUSP12-deficient mice exhibit high-fat diet (HFD)-induced and high-fat high-cholesterol diet-induced hyperinsulinemia and liver steatosis and decreased insulin sensitivity. Consistently, DUSP12 overexpression in hepatocyte could reduce HFD-induced hepatic steatosis, insulin resistance, and inflammation. At the molecular level, steatosis in the absence of DUSP12 was characterized by elevated apoptosis signal-regulating kinase 1 (ASK1), which mediates the mitogen-activated protein kinase (MAPK) pathway and hepatic metabolism. DUSP12 physically binds to ASK1, promotes its dephosphorylation, and inhibits its action on ASK1-related proteins, JUN N-terminal kinase, and p38 MAPK in order to inhibit lipogenesis under high-fat conditions. Conclusion: DUSP12 acts as a positive regulator in hepatic steatosis and offers potential therapeutic opportunities for NAFLD.

SUBMITTER: Huang Z

PROVIDER: S-EPMC6850665 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways.

Huang Zhen Z Wu Lei-Ming LM Zhang Jie-Lei JL Sabri Abdelkarim A Wang Shou-Jun SJ Qin Gui-Jun GJ Guo Chang-Qing CQ Wen Hong-Tao HT Du Bin-Bin BB Zhang Dian-Hong DH Kong Ling-Yao LY Tian Xin-Yu XY Yao Rui R Li Ya-Peng YP Liang Cui C Li Peng-Cheng PC Wang Zheng Z Guo Jin-Yan JY Li Ling L Dong Jian-Zeng JZ Zhang Yan-Zhou YZ

Hepatology (Baltimore, Md.) 20190422 4

Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Due to the growing economic burden of NAFLD on public health, it has become an emergent target for clinical intervention. DUSP12 is a member of the dual specificity phosphatase (DUSP) family, which plays important roles in brown adipocyte differentiation, microbial infection, and cardiac hypertrophy. However, the role of DUSP12 in NAFLD has yet to be clarified. Here, we reveal that DUSP1 ...[more]

PMID: 30820969

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Project description:Nonalcoholic fatty liver disease (NAFLD) is recognized as the liver component of metabolic syndrome. The regulation of hepatic lipid should be emphasized to prevent accompanying illness. As AMP-activated protein kinase (AMPK) and sterol regulatory element binding protein (SREBP) regulate lipid metabolism, CD36 and fatty acid synthase (FAS) promote lipid uptake and lipogenesis respectively, while acetyl-CoA carboxylase (ACC) is an indicator of negative feedback. The increase of IRS-1 phosphorylation at the residue ser307 (p-ser307-IRS-1) and decrease of p-ser473-Akt (p-Akt) are viewed as the insulin resistance markers, and our previous reports suggested dipeptidyl peptidase-4 (DPP-4) mediates insulin resistance, the crucial factor of metabolic syndrome. Abelmoschus esculentus (AE) fruit is well-known for its antidiabetic utility. We had isolated several AE subfractions by successive steps, and found that F1 and F2 were especially valid in suppressing DPP-4 signaling. Since little is known if AE works on NAFLD, now we first attempt to investigate whether AE is useful to attenuate hepatic lipogenesis and lipid uptake in liver cells, along with improving the metabolic targets. We demonstrated that AE subfractions attenuated the hepatic lipid accumulation induced by free fatty acids. Treatment of AE alleviated FAS and returned the level of p-ser79-ACC (p-ACC). Although F1 was more effective on AMPK, F2 seemed more stable to attenuate SREBP-1. Moreover, as fatty acids stimulated the expression of CD36, F2 showed a superior effect to down-regulate the lipid uptake. Both AE subfractions reduced the generation of ROS, decreased the level of p-ser307-IRS-1, and restored the expression of p-Akt. Moreover, treatment of DPP-4 inhibitor linagliptin revealed that, AE could prevent the hepatic lipogenesis, oxidative burden, and the related insulin resistance via downregulating DPP-4. In conclusion, the present investigation revealed that AE, especially F2, is potential to be developed as adjuvant to prevent NAFLD.

Dataset Information

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways.

Publications

Dual Specificity Phosphatase 12 Regulates Hepatic Lipid Metabolism Through Inhibition of the Lipogenesis and Apoptosis Signal-Regulating Kinase 1 Pathways.

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