Plasma mannose-binding lectin is stimulated by PPARα in humans

Rakhshandehroo, Maryam, Stienstra, Rinke, de Wit, Nicole J, Bragt, Marjolijn C E, Haluzik, Martin, Mensink, Ronald P, Müller, Michael ORCID: and Kersten, Sander (2012) Plasma mannose-binding lectin is stimulated by PPARα in humans. American Journal of Physiology - Endocrinology and Metabolism, 302 (5). E595-602. ISSN 1522-1555

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The peroxisome proliferator activated receptor-α (PPARα) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPARα 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 PPARα. Toward that aim, primary human hepatocytes were treated with the synthetic PPARα 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 PPARα activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPARα 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 PPARα and fenofibrate in humans, linking PPARα to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism.

Item Type: Article
Uncontrolled Keywords: adult,animals,cells, cultured,female,gene expression profiling,hepatocytes,humans,hyperlipidemias,hypolipidemic agents,male,mannose-binding lectin,mice,mice, knockout,middle aged,obesity,ppar alpha,peroxisome proliferators,rna, messenger,up-regulation,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine
Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User: Pure Connector
Date Deposited: 10 Jun 2014 20:34
Last Modified: 24 Oct 2022 06:06
DOI: 10.1152/ajpendo.00299.2011

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