title: Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion.
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 [(3)H]TG-labeled very low-density lipoprotein (VLDL)-like emulsion particles. An oral gavage of [(3)H]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.
authors.affiliation: Department of General Internal Medicine, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Irene O C M
authors.initials: IO
authors.lastname: Vroegrijk
authors.forename: Sjoerd A A
authors.initials: SA
authors.lastname: van den Berg
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvatori
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Hooiveld
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Cees J
authors.initials: CJ
authors.lastname: Tack
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Johannes W A
authors.initials: JW
authors.lastname: Smit
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Ko Willems
authors.initials: KW
authors.lastname: van Dijk
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D020170:Caspase 1 / Q000172:deficiency*; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000069463:Olive Oil; D010938:Plant Oils / Q000494:pharmacology; D019518:Postprandial Period / Q000187:drug effects; D014280:Triglycerides / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D008079:Lipoproteins, VLDL; D000069463:Olive Oil; D010938:Plant Oils; D014280:Triglycerides; D020170:Caspase 1