Given the importance of transcriptional regulation in metabolic control, we investigated the role of nuclear receptor co-factors in the liver, a key organ in energy homeostasis. Here we show in mice that the expression of receptor interacting protein 140 (RIP140) in the liver is induced in catabolic states like fasting and cancer cachexia. In contrast, chronic high fat diet feeding reduced RIP140 mRNA levels in the liver. Increased hepatic RIP140 in catabolic conditions was associated with an elevated hepatic triglyceride (TG) content (fatty liver) and decreased circulating TG levels, indicating a role of RIP140 in the transcriptional regulation of hepatic lipid metabolism. Indeed, an acute, liver-specific depletion of RIP140 through adenoviral-delivered shRNA expression decreased hepatic TG content and increased blood TG levels. The reduced expression of the lipid transporters caveolin and CD36 upon RIP140 knockdown might contribute to the observed decrease in liver TG content by reducing lipid influx into the liver. Interestingly, expression of SREBP-1c and FAS, genes involved in de novo lipogenesis were induced in RIP140-deficient livers, and consistently also hepatic VLDL-TG secretion was elevated. In addition, we observed a reduced expression of apolipoprotein A5 (ApoA5). ApoA5 has been shown to be involved in the control blood TG levels, at least in part, by accelerating the hydrolysis of triglycerides by lipoprotein lipase (LPL) for fatty acid uptake into adipose and muscle tissue. In agreement, we observed decreased LPL activity levels in white adipose tissue from mice with liver-specific RIP140 knockdown. Both, increased hepatic VLDL-TG secretion as well reduced LPL-dependent TG uptake by peripheral tissues might contribute to the observed elevation of serum TG levels. Our results suggest a crucial role of hepatic RIP140 in the metabolic control of processes associated with dyslipidimia in anorexia, cachexia and the metabolic syndrome.
03 - 07 May 2008
European Society of Endocrinology