Nutrient mTORC1 signaling contributes to hepatic lipid metabolism in the pathogenesis of non-alcoholic fatty liver disease

• Published in: Liver research Vol. 4; no. 1; pp. 15 - 22
• Main Author: Chen, Hanqing
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.03.2020; Chinese Academy of Sciences(CAS),Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety,Institute of High Energy Physics,CAS,Beijing,China; Department of Gastroenterology,Guangzhou Digestive Disease Center,Guangzhou First People's Hospital,School of Medicine,South China University of Technology,Guangzhou,Guangdong,China; KeAi Communications Co., Ltd
• Subjects: Autophagy; De novo lipogenesis; Mechanistic target of rapamycin; Non-alcoholic fatty liver disease; Nutrient signaling; Sterol regulatory element-binding proteins; Mechanistic target of rapamycin; Nutrient signaling; Non-alcoholic fatty liver disease; Autophagy; Sterol regulatory element-binding proteins; De novo lipogenesis
• DOI: 10.1016/j.livres.2020.02.004
• ISSN: 2542-5684; 2096-2878

Energy metabolism is maintained by the complex homeostatic system in multiple cells and organs involving “nutrient signaling” or “nutrient sensor”. Overnutrient-induced chronic metabolic diseases, as the hallmarks of the 21st century’s public health, are growing threat worldwide. In the past two decades, non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent form of chronic liver disease, affecting globally, and increases the risk of incident obesity, type 2 diabetes, and insulin resistance. NAFLD begins with the excessive triglyceride accumulation in hepatocytes, and develops to hepatocellular steatosis with inflammation (non-alcoholic steatohepatitis, NASH), fibrosis, cirrhosis, and ultimately hepatocellular carcinoma (HCC). The liver is the central mediator of lipid metabolism by regulation of fatty acid (FA) uptake, manufacture, store, export, and oxidation in response to physiological fluctuations of nutrient. Sterol regulatory element-binding protein c (SREBP-1c)- mediated de novo lipogenesis (DNL) is an important nutritional regulator in biosynthesis of FAs and triglyceride in the liver. Mechanistic target of rapamycin complex 1 (mTORC1), as a central hub of nutrient signaling, controls cellular metabolism and growth mainly via increasing anabolic processes and inhibiting catabolic processes in response to physiological fluctuations of nutrient. mTORC1 activation contributes to regulation of DNL by increasing SREBP1 transcription, which contributes to NAFLD pathogenesis and accelerates NAFLD-related HCC development. In this review, we provide the comprehensive understanding of the molecular mechanism of SREBPs and autophagy to control hepatic lipid homeostasis under nutrient availability in physiological and pathophysiological states, and highlight how nutrient mTORC1 signaling coordinately to integrate the lipid metabolic regulation and therapeutic targets in NAFLD and HCC.