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Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion

Author: Diepen, J.A. van · Stienstra, R. · Vroegrijk, I.O.C.M. · Berg, S.A.A. van den · Salvatori, D. · Hooiveld, G.J. · Kersten, S. · Tack, C.J. · Netea, M.G. · Smit, J.W.A. · Joosten, L.A.B. · Havekes, L.M. · Dijk, K.W. van · Rensen, P.C.N.
Type:article
Date:2013
Source:Journal of Lipid Research, 2, 54, 448-456
Identifier: 469513
doi: doi:10.1194/jlr.M031963
Keywords: Health · Absorption · Caspase-1 · Chylomicron · Intestine · Lipid · Liver · Metabolism · Triglyceride · VLDL · Healthy for Life · Healthy Living · Life · MHR - Metabolic Health Research · EELS - Earth, Environmental and Life Sciences

Abstract

Caspase-1 is known to activate the proinflammatory cytokines IL-1β and IL-18. Additionally, it can cleave other substrates, including proteins involved in metabolism. Recently, we showed that caspase-1 deficiency in mice strongly reduces high-fat diet-induced weight gain, at least partly caused by an increased energy production. Increased feces secretion by caspase-1-deficient mice suggests that lipid malabsorption possibly further reduces adipose tissue mass. In this study we investigated whether caspase-1 plays a role in triglyceride-(TG)-rich lipoprotein metabolism using caspase-1-deficient and wild-type mice. Caspase-1 deficiency reduced the postprandial TG response to an oral lipid load, whereas TG-derived fatty acid (FA) uptake by peripheral tissues was not affected, demonstrated by unaltered kinetics of [3H]TG- labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [3H]TG-containing olive oil revealed that caspase-1 deficiency reduced TG absorption and subsequent uptake of TG-derived FA in liver, muscle, and adipose tissue. Similarly, despite an elevated hepatic TG content, caspase-1 deficiency reduced hepatic VLDL-TG production. Intestinal and hepatic gene expression analysis revealed that caspase-1 deficiency did not affect FA oxidation or FA uptake but rather reduced intracellular FA transport, thereby limiting lipid availability for the assembly and secretion of TG-rich lipoproteins. The current study reveals a novel function for caspase-1, or caspase-1-cleaved substrates, in controlling intestinal TG absorption and hepatic TG secretion. Copyright © 2013 by the American Society for Biochemistry and Molecular Biology, Inc.