Loss of Acot12 contributes to NAFLD independent of lipolysis of adipose tissue

Sujeong Park,Kyu Yun Jang,Eun-Jung Jin,Peter K Kim,Chang Yeob Han,Jinsoo Song,Dae Won Jun,In-Jeoung Baek,Brian Raught

doi:10.1038/s12276-021-00648-1

Abstract

In this study, we hypothesized that deregulation in the maintenance of the pool of coenzyme A (CoA) may play a crucial role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Specific deletion of Acot12 (Acot12−/−), the major acyl-CoA thioesterase, induced the accumulation of acetyl-CoA and resulted in the stimulation of de novo lipogenesis (DNL) and cholesterol biosynthesis in the liver. KEGG pathway analysis suggested PPARα signaling as the most significantly enriched pathway in Acot12−/− livers. Surprisingly, the exposure of Acot12−/− hepatocytes to fenofibrate significantly increased the accumulation of acetyl-CoA and resulted in the stimulation of cholesterol biosynthesis and DNL. Interaction analysis, including proximity-dependent biotin identification (BioID) analysis, suggested that ACOT12 may directly interact with vacuolar protein sorting-associated protein 33A (VPS33A) and play a role in vesicle-mediated cholesterol trafficking and the process of lysosomal degradation of cholesterol in hepatocytes. In summary, in this study, we found that ACOT12 deficiency is responsible for the pathogenesis of NAFLD through the accumulation of acetyl-CoA and the stimulation of DNL and cholesterol via activation of PPARα and inhibition of cholesterol trafficking.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and occurs when fat accumulates due to factors that are closely associated with obesity and type 2 diabetes mellitus
ACOT12 is closely related to nonalcoholic fatty liver disease To identify the most relevant and responsible genes of the acetylCoA metabolic process (GO: 0006084) underlying the pathogenesis of NAFLD, we performed in silico analysis using Gene
Among key regulators in acetyl-coenzyme A (CoA) metabolism, the expression level of ACOT12 was the most significantly altered in both steatosis and Nonalcoholic steatohepatitis (NASH) compared to normal liver tissue, and its expression gradually changed during the progression of NAFLD (Fig. 1b and Supplementary Fig. 1)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and occurs when fat accumulates due to factors that are closely associated with obesity and type 2 diabetes mellitus. Even though NAFLD is an important risk factor and the leading cause of liver diseases, there is still no effective pharmaceutical treatment. The liver acts as the main regulator of lipid homeostasis by synthesizing fatty acids, oxidizing lipids, storing excess triglycerides (TGs), or taking up and releasing lipoproteins from/to other interacting organs, such as adipose tissue. The major function of adipose tissue is the storage and release of TGs and free fatty acids (FFAs) through lipogenesis and lipolysis, respectively[1]. It has been suggested that approximately 60% of hepatic TG comes from FFA pools of adipose tissue, and the rest comes from either de novo lipogenesis (DNL) or imbalanced nutrients by unhealthy diets[2]. Dysregulation in the interaction between adipose tissue and the liver in NAFLD is well described, the molecular and pathological mechanisms of NAFLD are not fully understood due to the multifaceted nature of NAFLD

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Conclusion