Apolipoprotein CIII as a therapeutic target in obesity-associated metabolic dysfunction

Apolipoprotein CIII (apoCIII) is a major regulator of lipid metabolism and increased levels are related to higher risk of cardiovascular disease. Increasing evidence, however, suggests that apoCIII may also play an important role in obesity-associated metabolic dysfunction and type 2 diabetes (T2D). ApoCIII inhibits lipoprotein lipase and hepatic lipases and impairs the hepatic clearance of triglyceride-rich lipoproteins, thereby promoting hypertriglyceridemia. In addition, apoCIII has been implicated in inflammatory processes that may contribute to metabolic and vascular disease. Importantly, insulin and glucose regulate apoCIII expression, providing a mechanistic link between apoCIII and the metabolic disturbances associated with obesity and diabetes. In this review, we summarize current evidence concerning the relationship between apoCIII and obesity-associated metabolic dysfunction. Diet-induced and genetic models of obesity exhibit elevated circulating apoCIII levels as well as increased apoCIII expression in pancreatic islets. Elevated apoCIII is associated with impaired lipid metabolism, adipose tissue dysfunction, inflammation, insulin resistance, and disturbed glucose homeostasis. Conversely, pharmacological reduction of apoCIII using antisense oligonucleotides improves the metabolic dysfunctions. These effects appear to involve mechanisms extending beyond triglyceride lowering, including enhanced lipoprotein clearance, increased hepatic fatty-acid oxidation and ketogenesis, and increased thermogenic activity in adipose tissue. Preliminary clinical evidence suggests that apoCIII reduction may also improve lipid and glucose metabolism and insulin sensitivity in individuals with obesity, T2D, and hypertriglyceridemia. ApoCIII therefore represents a potential therapeutic target in obesity-associated metabolic disease. Further clinical studies are needed to establish the efficacy, safety, and long-term metabolic effects of targeted apoCIII lowering in obesity and diabetes in humans.