Abstract
The peroxisome proliferator activated receptor-alpha (PPAR alpha) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPAR alpha on lipid metabolism are partially mediated by circulating proteins such as FGF21 and ANGPTL4.
The present study was undertaken to screen for and identify circulating proteins produced by human liver that are under the control of PPAR alpha. Toward that aim, primary human hepatocytes were treated with the synthetic PPAR alpha agonist Wy-14643 and whole genome expression data selected for secreted proteins.
Expression of FGF21, ANGPTL4, and mannose-binding lectin (MBL), a soluble mediator of innate immunity and primary component of the lectin branch of the complement system, was markedly upregulated by Wy-14643 in primary human hepatocytes. Mice express two MBL isomers, Mbl1 and Mbl2.
Mbl1 mRNA was weakly induced by Wy-14643 in primary mouse hepatocytes and remained unaltered by Wy-14643 in mouse liver. Mbl2 mRNA was unchanged by Wy-14643 in primary mouse hepatocytes and was strongly reduced by Wy-14643 in mouse liver.
Remarkably, plasma Mbl1 levels were increased by chronic PPAR alpha activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPAR alpha agonist fenofibrate at 200 mg/day for 6 wk and 3 mo increased plasma MBL levels by 73 (P = 0.0016) and 86% (P = 0.017), respectively.
It is concluded that hepatocyte gene expression and plasma levels of MBL are stimulated by PPAR alpha and fenofibrate in humans, linking PPAR alpha to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism.