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

J.A. van Diepen, R. Stienstra, I.O.C.M. Vroegrijk, S.A.A. van den Berg, D. Salvatori, G.J.E.J. Hooiveld, A.H. Kersten, C.J. Tack, M.G. Netea, J.W.A. Smit, L.A.B. Joosten, L.M. Havekes, K.W. van Dijk, P.C.N. Rensen

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Abstract

Caspase-1 is known to activate the proinflammatory cytokines IL-1 beta 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 [H-3] TG-labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [H-3] 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.(jlr) The current study reveals a novel function for caspase-1, or caspase-1-cleaved substrates, in controlling intestinal TG absorption and hepatic TG secretion.-van Diepen, J. A., R. Stienstra, I. O. C. M. Vroegrijk, S. A. A. van den Berg, D. Salvatori, G. J. Hooiveld, S. Kersten, C. J. Tack, M. G. Netea, J. W. A. Smit, L. A. B. Joosten, L. M. Havekes, K. W. van Dijk, and P. C. N. Rensen. Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion. J. Lipid Res. 2013. 54: 448-456.
Original languageEnglish
Pages (from-to)448-456
JournalJournal of Lipid Research
Volume54
Issue number2
DOIs
Publication statusPublished - 2013

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Keywords

  • lipid-metabolism
  • adipose-tissue
  • fatty-acids
  • lipoprotein metabolism
  • insulin-resistance
  • immune-responses
  • inflammation
  • liver
  • inflammasomes
  • interleukin-1

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