title: Apolipoprotein B secretion is regulated by hepatic triglyceride, and not insulin, in a model of increased hepatic insulin signaling.
abstract: OBJECTIVE
  States of insulin resistance, hyperinsulinemia, and hepatic steatosis are associated with increased secretion of triglycerides (TG) and apolipoprotein B (apoB), even though insulin targets apoB for degradation. We used hepatic-specific "phosphatase and tensin homologue deleted on chromosome 10" (Pten) knockout (hPten-ko) mice, with increased hepatic insulin signaling, to determine the relative roles of insulin signaling and hepatic TG in regulating apoB secretion.
  
  
  RESULTS
  TG and apoB secretion was elevated in hPten-ko mice. When hepatic TG was reduced by inhibition of diacylglycerol acyltransferase 1/diacylglycerol acyltransferase 2 or sterol regulatory element-binding protein-1c, both TG secretion and apoB secretion fell without changes in hepatic insulin signaling. Acute reconstitution of hPten reduced hepatic TG content, and both TG and apoB secretion fell within 4 days despite decreased hepatic insulin signaling. Acute depletion of hepatic Pten by adenoviral introduction of Cre into Pten floxed mice caused steatosis within 4 days, and secretion of both TG and apoB increased despite increased hepatic insulin signaling. Even when steatosis after acute Pten depletion was prevented by pretreatment with SREBP-1c antisense oligonucleotides, apoB secretion was not reduced after 4 days. Ex vivo results were in primary hepatocytes were similar.
  
  
  CONCLUSIONS
  Either hepatic TG is the dominant regulator of apoB secretion or any inhibitory effects of hepatic insulin signaling on apoB secretion is very short-lived.
authors.affiliation: Irving Institute for Clinical and Translational Research, PH10-305, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Byoung C
authors.initials: BC
authors.lastname: Moon
authors.forename: Antonio
authors.initials: A
authors.lastname: Hernandez-Ono
authors.forename: Bangyan
authors.initials: B
authors.lastname: Stiles
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D051048:Diacylglycerol O-Acyltransferase / Q000172:deficiency / Q000235:genetics; D005234:Fatty Liver / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050155:Lipogenesis / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001055:Apolipoproteins B; D007328:Insulin; D014280:Triglycerides; C516957:DGAT2 protein, mouse; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse