Control of hepatic and systemic lipid metabolism through the nuclear receptor co-factor RIP140

Abstract

Hypertriglyceridemia forms a hallmark of the metabolic syndrome and represents an independent risk factor for the development of coronary heart disease. Plasma lipid levels are controlled through a complex interplay between different tissues, the molecular basis of which remains largely unknown. Given the importance of transcriptional regulation in metabolic control, we investigated the role of nuclear receptor co-factor receptor interacting protein 140 (RIP140) in the liver, a key organ in energy homeostasis. Here we show that an acute, liver-specific depletion of RIP140 caused dramatically increased blood triglyceride levels. In contrast, hepatic triglyceride content in these animals was decreased in the absence of RIP140, suggesting that the observed hypertriglyceridemia was not the consequence of increased hepatic VLDL production. Interestingly, RIP140 knockdown in the liver reduced expression of apolipoprotein A5 (ApoA5), the serum levels of which have been shown to be inversely correlated with circulating blood triglycerides. Indeed, RIP140 knockdown in a murine hepatocyte cell line decreased ApoA5 promoter activity in transient transfection studies. Conversely, RIP140 over-expression induced ApoA5 expression in these cells, strengthening the notion that RIP140 acts as a direct transcriptional co-activator on the ApoA5 promoter. ApoA5 has been shown to control blood lipid levels, at least in part, by accelerating the hydrolysis of triglycerides by lipoprotein lipase (LPL) in adipose and muscle tissue. By influencing hepatic ApoA5 release, transcriptional control via RIP140 in the liver might, therefore, provide a novel mechanism of metabolic tissue crosstalk and the development of dyslipidemia associated with the metabolic syndrome.