Plasma mannose-binding lectin is stimulated by PPARα in humans

M. Rakhshandehroo, R. Stienstra, N.J. de Wit, M.C. Bragt, M. Haluzik, R.P. Mensink, M. Muller, S. Kersten

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The Peroxisome Proliferator Activated Receptor alpha (PPARalpha) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPARalpha 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 control of PPARalpha. Towards that aim, primary human hepatocytes were treated with the synthetic PPARalpha agonist Wy14643 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 Wy14643 in primary human hepatocytes. Mice express two MBL isomers: Mbl1 and Mbl2. Mbl1 mRNA was weakly induced by Wy14643 in primary mouse hepatocytes and remained unaltered by Wy14643 in mouse liver. Mbl2 mRNA was unchanged by Wy14643 in primary mouse hepatocytes and was strongly reduced by Wy14643 in mouse liver. Remarkably, plasma Mbl1 levels were increased by chronic PPARalpha activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPARalpha-agonist fenofibrate at 200 mg/day for 6 week and 3 months increased plasma MBL levels by 73% (P=0.0016) and 86% (P=0.017), respectively. It is concluded that hepatic gene expression and plasma levels of MBL are stimulated by PPARalpha and fenofibrate in humans, linking PPARalpha to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism.
Original languageEnglish
Pages (from-to)E595-E602
Number of pages8
JournalAmerican Journal of Physiology : Endocrinology and Metabolism
Volume302
Issue number5
DOIs
Publication statusPublished - Mar 2012

Keywords

  • liver
  • fibrates
  • peroxisome proliferator-activated receptor-alpha
  • complement
  • PROLIFERATOR-ACTIVATED RECEPTORS
  • HEPATIC LIPID-METABOLISM
  • FATTY LIVER-DISEASE
  • FASTING RESPONSE
  • MOUSE
  • GENE
  • FIBROBLAST-GROWTH-FACTOR-21
  • INFLAMMATION
  • FENOFIBRATE
  • REGULATOR

Cite this

Rakhshandehroo, M., Stienstra, R., de Wit, N. J., Bragt, M. C., Haluzik, M., Mensink, R. P., Muller, M., & Kersten, S. (2012). Plasma mannose-binding lectin is stimulated by PPARα in humans. American Journal of Physiology : Endocrinology and Metabolism, 302(5), E595-E602. https://doi.org/10.1152/ajpendo.00299.2011