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 HFDinduced 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 mitogenactivated 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. (Hepatology 2019;70:1099-1118). SEE EDITORIAL ON PAGE 1091N onalcoholic fatty liver disease (NAFLD) is the most common diffuse liver disease and is characterized by lipid accumulation in hepatocytes in the absence of excessive alcohol consumption. (1) The prevalence of NAFLD increases worryingly with obesity and other diseases of metabolic syndrome (MS) and is expected to be the leading cause of liver failure in the future. (2) Accumulating studies show that NAFLD not only is linked to an increased risk of liver-related mortality or morbidity

Melatonin safeguards against fatty liver by antagonizing TRAFs‐mediated ASK1 deubiquitination and stabilization in a β‐arrestin‐1 dependent manner

“…As a MAPKKK, ASK1 acts as a master switch of cell death: it initiates and sustains activation of two MAPKs (p38 and JNK) to induce apoptosis. Since ASK1 is over‐activated in liver tissues during NAFLD, ASK1 critically involved in liver inflammation and thought to be an ideal druggable target of NAFLD . Based on our findings, inhibition on the activation of ASK1 pathway and its downstream JNK and p38 signals by melatonin could be a promising strategy to alleviate NAFLD.…”

“…Thus, ASK1 is involved in the development of various diseases, including tumorigenesis, neutrophilic dermatosis, cardiac hypertrophy, diabetes, and acquired immunodeficiency syndrome . For the past few years, several investigations have showed that ASK1 is continuously over‐activated in liver during NAFLD progression, and inactivation of ASK1 might remedy NAFLD . A very recent clinical study showed that a selective ASK1 inhibitor reduced liver fibrosis in patients with NASH …”

ASKing No More: The Emerging Role of Dual‐Specific Phosphatase 12 in the Regulation of Hepatic Lipid Metabolism

“…In this issue of Hepatology , Huang and colleagues report a very interesting study addressing the regulatory mechanisms underlying ASK1 activation. Using gain‐of‐function and loss‐of‐function studies in vitro and in vivo , they show that DUSP12, a member of the dual‐specific phosphatase (DUSP) family, regulates hepatic lipotoxicity through inhibition of the ASK1 signal cascade (Fig.…”

“…Using gain‐of‐function and loss‐of‐function studies in vitro and in vivo , they show that DUSP12, a member of the dual‐specific phosphatase (DUSP) family, regulates hepatic lipotoxicity through inhibition of the ASK1 signal cascade (Fig. ) …”

“…However, their mechanisms of action are still poorly understood. Huang et al show that in livers of mice fed a high‐fat diet (HFD) the expression of DUSP12 is significantly lower than that in liver samples of normal lean animals. Compared to untreated immortalized hepatocytes, DUSP12 expression levels are also lower in hepatocytes cultured in the presence of palmitic acid and oleic acid, the most abundant fatty acids in Western diets.…”