title: Prevention of hepatic fibrosis with liver microsomal triglyceride transfer protein deletion in liver fatty acid binding protein null mice.
abstract: Blocking hepatic very low-density lipoprotein secretion through genetic or pharmacologic inhibition of microsomal triglyceride transfer protein (Mttp) causes hepatic steatosis, yet the risks for developing hepatic fibrosis are poorly understood. We report that liver-specific Mttp knockout mice (Mttp-LKO) exhibit both steatosis and fibrosis, which is exacerbated by a high-transfat/fructose diet. When crossed into germline liver fatty acid (FA) binding protein null mice (Mttp-LKO, i.e., double knockout mice) hepatic steatosis was greatly diminished and fibrosis prevented, on both low-fat and high-fat diets. The mechanisms underlying protection include reduced long chain FA uptake, shifts in FA distribution (lipidomic profiling), and metabolic turnover, specifically decreased hepatic 18:2 FA and triglyceride species and a shift in 18:2 FA use for oxidation versus incorporation into newly synthesized triglyceride. Double knockout mice were protected against fasting-induced hepatic steatosis (a model of enhanced exogenous FA delivery) yet developed steatosis upon induction of hepatic de novo lipogenesis with fructose feeding. Mttp-LKO mice, on either the liver FA binding protein null or Apobec-1 null background (i.e., apolipoprotein B100 only) exhibited only subtle increases in endoplasmic reticulum stress, suggesting that an altered unfolded protein response is unlikely to account for the attenuated phenotype in double knockout mice. Acute, antisense-mediated liver FA binding protein knockdown in Mttp-LKO mice also reduced FA uptake, increased oxidation versus incorporation of 18:2 species with complete reversal of hepatic steatosis, increased hepatic injury, and worsened fibrosis.
  
  
  
  Perturbing exogenous hepatic FA use modulates both hepatic steatosis and fibrosis in the setting of hepatic Mttp deletion, adding new insight into the pathophysiological mechanisms and consequences of defective very low-density lipoprotein secretion. (Hepatology 2017;65:836-852).
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Newberry
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kennedy
authors.affiliation: Ionis Pharmaceuticals, Inc., Carlsbad, CA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Ionis Pharmaceuticals, Inc., Carlsbad, CA.
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pathology, St. Louis University, St. Louis, MO.
authors.forename: Anping
authors.initials: A
authors.lastname: Chen
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO.
authors.forename: Nicholas O
authors.initials: NO
authors.lastname: Davidson
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D015243:Cholesterol, VLDL / Q000378:metabolism; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000235:genetics* / Q000502:physiology; D050155:Lipogenesis / Q000502:physiology; D008103:Liver Cirrhosis / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D011897:Random Allocation; D012016:Reference Values
chemical_list: D002352:Carrier Proteins; D015243:Cholesterol, VLDL; D050556:Fatty Acid-Binding Proteins; C106092:microsomal triglyceride transfer protein