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HORMONES AND SIGNALING

LXR activation perturbs hepatic insulin signaling and stimulates production of apolipoprotein B-containing lipoproteins

Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Submitted 14 September 2008 ; accepted in final form 2 June 2009

Liver X receptor- (LXR) is considered a master regulator of hepatic lipid metabolism; however, little is known about the link between LXR activation, hepatic insulin signaling, and very low-density lipoprotein (VLDL)-apolipoprotein B (apoB) assembly and secretion. Here, we examined the effect of LXR activation on hepatic insulin signaling and apoB-lipoprotein production. In vivo activation of LXR for 7 days using a synthetic LXR agonist, TO901317, in hamsters led to increased plasma triglyceride (TG; 3.6-fold compared with vehicle-treated controls, P = 0.006), apoB (54%, P < 0.0001), and VLDL-TG (eightfold increase compared with vehicle). As expected, LXR stimulation activated maturation of sterol response element binding protein-1c (SREBP-1c) as well as the SREBP-1c target genes steroyl CoA desaturase (SCD) and fatty acid synthase (FAS). Metabolic pulse-chase labeling experiments in primary hamster hepatocytes showed increased stability and secretion of newly synthesized apoB following LXR activation. Microsomal triglyceride transfer protein (MTP) mRNA and protein were unchanged, however, likely because of the relatively short period of treatment and long half-life of MTP mRNA. Examination of hepatic insulin-signaling molecules revealed LXR-mediated reductions in insulin receptor (IR)β subunit mass (39%, P = 0.014) and insulin receptor substrate (IRS)-1 tyrosine phosphorylation (24%, P = 0.023), as well as increases in protein tyrosine phosphatase (PTP)1B (29%, P < 0.001) protein mass. In contrast to IRS-1, a twofold increase in IRS-2 mass (228%, P = 0.0037) and a threefold increase in IRS-2 tyrosine phosphorylation (321%, P = 0.012) were observed. In conclusion, LXR activation dysregulates hepatic insulin signaling and leads to a considerable increase in the number of circulating TG-rich VLDL-apoB particles, likely due to enhanced hepatic assembly and secretion of apoB-containing lipoproteins.

liver X receptor; very low-density lipoprotein; hamster