{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:51:46Z","timestamp":1790707906415,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2017,1,19]],"date-time":"2017-01-19T00:00:00Z","timestamp":1484784000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1"},{"start":{"date-parts":[[2017,1,19]],"date-time":"2017-01-19T00:00:00Z","timestamp":1484784000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2017,3]]},"abstract":"<jats:p>Blocking hepatic very low\u2010density 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\u2010specific Mttp knockout mice (Mttp\u2010LKO) exhibit both steatosis and fibrosis, which is exacerbated by a high\u2010transfat\/fructose diet. When crossed into germline liver fatty acid (FA) binding protein null mice (Mttp\u2010LKO, i.e., double knockout mice) hepatic steatosis was greatly diminished and fibrosis prevented, on both low\u2010fat and high\u2010fat 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\u2010induced hepatic steatosis (a model of enhanced exogenous FA delivery) yet developed steatosis upon induction of hepatic <jats:italic toggle=\"yes\">de novo<\/jats:italic> lipogenesis with fructose feeding. Mttp\u2010LKO mice, on either the liver FA binding protein null or Apobec\u20101 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\u2010mediated liver FA binding protein knockdown in Mttp\u2010LKO 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. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> 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\u2010density lipoprotein secretion. (H<jats:sc>epatology<\/jats:sc> 2017;65:836\u2010852).<\/jats:p>","DOI":"10.1002\/hep.28941","type":"journal-article","created":{"date-parts":[[2016,11,16]],"date-time":"2016-11-16T16:29:14Z","timestamp":1479313754000},"page":"836-852","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":26,"title":["Prevention of hepatic fibrosis with liver microsomal triglyceride transfer protein deletion in liver fatty acid binding protein null mice"],"prefix":"10.1097","volume":"65","author":[{"given":"Elizabeth P.","family":"Newberry","sequence":"first","affiliation":[{"name":"Department of Medicine,Washington University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Medicine,Washington University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Medicine,Washington University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J.","family":"Graham","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.,Carlsbad,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanne M.","family":"Crooke","sequence":"additional","affiliation":[{"name":"Ionis Pharmaceuticals, Inc.,Carlsbad,CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Medicine,Washington University School of Medicine,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anping","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology,St. Louis University,St. Louis,MO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel 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