title: Compensatory increase in hepatic lipogenesis in mice with conditional intestine-specific Mttp deficiency.
abstract: Microsomal TG transfer protein (MTTP) is required for the assembly and secretion of TG (TG)-rich lipoproteins from both enterocytes and hepatocytes. Liver-specific deletion of Mttp produced a dramatic reduction in plasma very low density lipoprotein-TG and virtually eliminated apolipoprotein B100 (apoB100) secretion yet caused only modest reductions in plasma apoB48 and apoB48 secretion from primary hepatocytes. These observations prompted us to examine the phenotype following intestine-specific Mttp deletion because murine, like human enterocytes, secrete virtually exclusively apoB48. We generated mice with conditional Mttp deletion in villus enterocytes (Mttp-IKO), using a tamoxifen-inducible, intestine-specific Cre transgene. Villus enterocytes from chow-fed Mttp-IKO mice contained large cytoplasmic TG droplets and no chylomicron-sized particles within the secretory pathway. Chow-fed, Mttp-IKO mice manifested steatorrhea, growth arrest, and decreased cholesterol absorption, features that collectively recapitulate the phenotype associated with abetalipoproteinemia. Chylomicron secretion was reduced dramatically in vivo, in conjunction with an approximately 80% decrease in apoB48 secretion from primary enterocytes. Additionally, although plasma and hepatic cholesterol and TG content were decreased, Mttp-IKO mice demonstrated a paradoxical increase in both hepatic lipogenesis and very low density lipoprotein secretion. These findings establish distinctive features for MTTP involvement in intestinal chylomicron assembly and secretion and suggest that hepatic lipogenesis undergoes compensatory induction in the face of defective intestinal TG secretion.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Newberry
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Sylvie
authors.initials: S
authors.lastname: Robine
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Jinny S
authors.initials: JS
authors.lastname: Wong
authors.forename: Jianyang
authors.initials: J
authors.lastname: Luo
authors.forename: Susan
authors.initials: S
authors.lastname: Kennedy
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Davidson
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002914:Chylomicrons / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain
chemical_list: D002352:Carrier Proteins; D002914:Chylomicrons; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; D006903:Hydroxymethylglutaryl CoA Reductases