Insulin Concentration Modulates Hepatic Lipid Accumulation in Mice in Part via Transcriptional Regulation of Fatty Acid Transport Proteins

被引:27
作者
Softic, Samir [1 ,2 ]
Kirby, Michelle [1 ]
Berger, Nicholas G. [1 ]
Shroyer, Noah F. [1 ,3 ]
Woods, Stephen C. [4 ]
Kohli, Rohit [1 ]
机构
[1] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Cincinnati, OH USA
[2] Indiana Univ, James Whitcomb Riley Hosp Children, Dept Pediat, Indianapolis, IN USA
[3] Cincinnati Childrens Hosp Med Ctr, Div Dev Biol, Cincinnati, OH USA
[4] Univ Cincinnati Coll Med, Dept Psychiat & Behav Neurosci, Metab Dis Inst, Obes Res Ctr, Cincinnati, OH USA
关键词
ACYL-COA SYNTHETASE; LIVER-DISEASE; IN-VIVO; NONALCOHOLIC STEATOHEPATITIS; RECEPTOR SUBSTRATE-2; GENE-EXPRESSION; IRS-2; METABOLISM; STEATOSIS; PATHWAY;
D O I
10.1371/journal.pone.0038952
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. Methods/Principal Findings: 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/Significance: 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.
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页数:11
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