The Nuclear Envelope in Lipid Metabolism and Pathogenesis of NAFLD

SIMPLE SUMMARY: The liver is a major organ regulating lipid metabolism and a proper liver function is essential to health. Nonalcoholic fatty liver disease (NAFLD) is a condition with abnormal fat accumulation in the liver without heavy alcohol use. NAFLD is becoming one of the most common liver diseases with the increase in obesity in many parts of the world. There is no approved cure for the disease and a better understanding of disease mechanism is needed for effective prevention and treatment. The nuclear envelope, a membranous structure that surrounds the cell nucleus, is connected to the endoplasmic reticulum where the vast majority of cellular lipids are synthesized. Growing evidence indicates that components in the nuclear envelope are involved in cellular lipid metabolism. We review published studies with various cell and animal models, indicating the essential roles of nuclear envelope proteins in lipid metabolism. We also discuss how defects in these proteins affect cellular lipid metabolism and possibly contribute to the pathogenesis of NAFLD. ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a burgeoning public health problem worldwide. Despite its tremendous significance for public health, we lack a comprehensive understanding of the pathogenic mechanisms of NAFLD and its more advanced stage, nonalcoholic steatohepatitis (NASH). Identification of novel pathways or cellular mechanisms that regulate liver lipid metabolism has profound implications for the understanding of the pathology of NAFLD and NASH. The nuclear envelope is topologically connected to the ER, where protein synthesis and lipid synthesis occurs. Emerging evidence points toward that the nuclear lamins and nuclear membrane-associated proteins are involved in lipid metabolism and homeostasis. We review published reports that link these nuclear envelope proteins to lipid metabolism. In particular, we focus on the recent work demonstrating the essential roles for the nuclear envelope-localized torsinA/lamina-associated polypeptide (LAP1) complex in hepatic steatosis, lipid secretion, and NASH development. We also discuss plausible pathogenic mechanisms by which the loss of either protein in hepatocytes leads to hepatic dyslipidemia and NASH development.