title: Insulin concentration modulates hepatic lipid accumulation in mice in part via transcriptional regulation of fatty acid transport proteins.
abstract: BACKGROUND
  Fatty liver disease (FLD) is commonly associated with insulin resistance and obesity, but interestingly it is also observed at low insulin states, such as prolonged fasting. Thus, we asked whether insulin is an independent modulator of hepatic lipid accumulation.
  
  
  RESULTS
  In mice we induced, hypo- and hyperinsulinemia associated FLD by diet induced obesity and streptozotocin treatment, respectively. The mechanism of free fatty acid induced steatosis was studied in cell culture with mouse liver cells under different insulin concentrations, pharmacological phosphoinositol-3-kinase (PI3K) inhibition and siRNA targeted gene knock-down. We found with in vivo and in vitro models that lipid storage is increased, as expected, in both hypo- and hyperinsulinemic states, and that it is mediated by signaling through either insulin receptor substrate (IRS) 1 or 2. As previously reported, IRS-1 was up-regulated at high insulin concentrations, while IRS-2 was increased at low levels of insulin concentration. Relative increase in either of these insulin substrates, was associated with an increase in liver-specific fatty acid transport proteins (FATP) 2&5, and increased lipid storage. Furthermore, utilizing pharmacological PI3K inhibition we found that the IRS-PI3K pathway was necessary for lipogenesis, while FATP responses were mediated via IRS signaling. Data from additional siRNA experiments showed that knock-down of IRSs impacted FATP levels.
  
  
  CONCLUSIONS
  States of perturbed insulin signaling (low-insulin or high-insulin) both lead to increased hepatic lipid storage via FATP and IRS signaling. These novel findings offer a common mechanism of FLD pathogenesis in states of both inadequate (prolonged fasting) and ineffective (obesity) insulin signaling.
authors: Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
authors: Samir
authors: S
authors: Softic
authors: Michelle
authors: M
authors: Kirby
authors: Nicholas G
authors: NG
authors: Berger
authors: Noah F
authors: NF
authors: Shroyer
authors: Stephen C
authors: SC
authors: Woods
authors: Rohit
authors: R
authors: Kohli
mesh_terms: D000410:Alanine Transaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: D050612:Fatty Acid Transport Proteins; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D014280:Triglycerides; D000410:Alanine Transaminase