TY - JOUR
T1 - Hepatic insulin receptor deficiency impairs the SREBP-2 response to feeding and statins
AU - Miao, Ji
AU - Haas, Joel T.
AU - Manthena, Praveen
AU - Wang, Yanning
AU - Zhao, Enpeng
AU - Vaitheesvaran, Bhavapriya
AU - Kurland, Irwin J.
AU - Biddinger, Sudha B.
PY - 2014/4
Y1 - 2014/4
N2 - The liver plays a central role in metabolism and mediating insulin action. To dissect the effects of insulin on the liver in vivo, we have studied liver insulin receptor knockout (LIRKO) mice. Because LIRKO livers lack insulin receptors, they are unable to respond to insulin. Surprisingly, the most profound derangement observed in LIRKO livers by microarray analysis is a suppression of the cholesterologenic genes. Sterol regulatory element binding protein (SREBP)-2 promotes cholesterologenic gene transcription, and is inhibited by intracellular cholesterol. LIRKO livers show a slight increase in hepatic cholesterol, a 40% decrease in Srebp-2, and a 50-90% decrease in the cholesterologenic genes at the mRNA and protein levels. In control mice, SREBP-2 and cholesterologenic gene expression are suppressed by fasting and restored by refeeding; in LIRKO mice, this response is abolished. Similarly, the ability of statins to induce Srebp-2 and the cholesterologenic genes is lost in LIRKO livers. In contrast, ezetimibe treatment robustly induces Srepb-2 and its targets in LIRKO livers, raising the possibility that insulin may regulate SREBP-2 indirectly, by altering the accumulation or distribution of cholesterol within the hepatocyte. Taken together, these data indicate that cholesterol synthesis is a key target of insulin action in the liver.
AB - The liver plays a central role in metabolism and mediating insulin action. To dissect the effects of insulin on the liver in vivo, we have studied liver insulin receptor knockout (LIRKO) mice. Because LIRKO livers lack insulin receptors, they are unable to respond to insulin. Surprisingly, the most profound derangement observed in LIRKO livers by microarray analysis is a suppression of the cholesterologenic genes. Sterol regulatory element binding protein (SREBP)-2 promotes cholesterologenic gene transcription, and is inhibited by intracellular cholesterol. LIRKO livers show a slight increase in hepatic cholesterol, a 40% decrease in Srebp-2, and a 50-90% decrease in the cholesterologenic genes at the mRNA and protein levels. In control mice, SREBP-2 and cholesterologenic gene expression are suppressed by fasting and restored by refeeding; in LIRKO mice, this response is abolished. Similarly, the ability of statins to induce Srebp-2 and the cholesterologenic genes is lost in LIRKO livers. In contrast, ezetimibe treatment robustly induces Srepb-2 and its targets in LIRKO livers, raising the possibility that insulin may regulate SREBP-2 indirectly, by altering the accumulation or distribution of cholesterol within the hepatocyte. Taken together, these data indicate that cholesterol synthesis is a key target of insulin action in the liver.
KW - Cholesterol bio-synthesis
KW - Hepatic insulin signaling
KW - Liver insulin receptor knockout
KW - Sterol regulatory element binding protein
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U2 - 10.1194/jlr.M043711
DO - 10.1194/jlr.M043711
M3 - Article
C2 - 24516236
AN - SCOPUS:84897387992
SN - 0022-2275
VL - 55
SP - 659
EP - 667
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 4
ER -