Regulation of hepatic triglyceride metabolism by adipose differentiation-related protein

The liver stores triglycerides to provide energy upon demand. Excessive accumulation of hepatic triglycerides, known as hepatic steatosis, is associated with insulin resistance, cardiovascular disease, and obesity. Moreover, fatty liver is the initial stage of a spectrum of liver damage that can progress to steatohepatitis, cirrhosis, and liver failure. Within the liver, triglycerides are accumulated into lipid droplets associated with Adipose differentiation-related protein (ADRP). ADRP is a lipid droplet protein whose levels parallel intracellular triglyceride content. Indeed, ADRP levels are increased in mouse models of fatty liver. Reduction of ADRP levels in obese mouse models of fatty liver decreases hepatic triglyceride content and improves insulin sensitivity suggesting a crucial role for ADRP in triglyceride metabolism and energy homeostasis. Here we examine how ADRP regulates hepatic triglyceride accumulation and the implications of ADRP-mediated steatosis in the development of hepatic insulin resistance and steatohepatitis. We demonstrate that ADRP is required for diet-induced fatty liver. A reduction of hepatic ADRP expression by antisense oligonucleotides (ADRP ASO) prevents hepatic insulin resistance associated with fatty liver by decreasing hepatic triglyceride and diacylglycerol content and decreasing the enzymatic activity of diacylglycerol acyltransferase-2 (DGAT2). Suppression of triglyceride accumulation by ADRP ASO conserved hepatic insulin sensitivity by preserving insulin-mediated suppression of hepatic glucose production. Next, we characterized the means by which ADRP mediates triglyceride accumulation and found that ADRP facilitates this process by decreasing the rate of triglyceride turnover in primary mouse hepatocytes. Moreover, reduction of ADRP levels decreased the expression of lipogenic and lipolytic genes in vivo and in vitro suggesting that ADRP is necessary for optimal lipid metabolism. We further examined the association between ADRP-mediated steatosis and the development of inflammation in two mouse models of steatohepatitis. Reduction of hepatic ADRP levels increased the expression of pro-inflammatory cytokines and the presence of macrophages in the livers of these mice which worsened the inflammatory response. Collectively, these findings indicate that ADRP mediates hepatic triglyceride accumulation by regulating triglyceride synthesis and hydrolysis which affect hepatic lipid metabolism, insulin sensitivity, and inflammation.