Obesity, diabetes mellitus, and liver fibrosis

Abstract

Obesity is a global epidemic with more than 1 billion overweight adults and at least 300 million obese patients worldwide. Diabetes is characterized by a defect in insulin secretion or a decrease in sensitivity to insulin, which results in elevated fasting blood glucose. Both obesity and elevated fasting glucose are risk factors for nonalcoholic fatty liver disease, a disease spectrum that includes hepatic steatosis (nonalcoholic fatty liver), nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Increased adiposity and insulin resistance contribute to the progression from NASH to fibrosis through the development of a profibrotic mileau in the liver, including increased hepatocellular death, increased reactive oxygen species generation, and an altered adipokine/cytokine balance. This review will summarize recent advances in our understanding of the pathological interactions among excessive fat accumulation, insulin resistance, and hepatic fibrogenesis and discuss specific molecular pathways that may be of interest in the development of therapeutic interventions to prevent and/or reverse hepatic fibrosis.

Fig. 1.

Proposed mechanisms of interaction among obesity, insulin resistance, and nonalcoholic fatty liver disease (NAFLD). The mediators are color-coded based on the source of origin (red, liver; brown, adipose tissue). FFA, free fatty acid; TG, triglyceride; SREBP1c, sterol regulatory element-binding protein 1c; ACC, acetyl-CoA carboxylase; FAS, fatty acid synthase; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; SOCS-3, suppressor of cytokine signaling-3; JNK, c-Jun NH₂-terminal kinase.

Fig. 2.

Potential pharmaceutical targets of interest in the progression of nonalcoholic steatohepatitis (NASH) to fibrosis in the setting of obesity and insulin resistance. ROS, reactive oxygen species; TGF-β, transforming growth factor-β; MCP-1, monocyte chemoattractant protein-1; CTGF, connective tissue growth factor.