LXRalpha activation perturbs hepatic insulin signaling and stimulates production of apolipoprotein B-containing lipoproteins.
Liver X receptor-alpha (LXRalpha) 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 LXRalpha activation on hepatic insulin signaling and apoB-lipoprotein production. In vivo activation of LXRalpha 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)beta 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.
Basciano
Heather
H
Molecular Structure and Function, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Miller
Abigale
A
Baker
Chris
C
Naples
Mark
M
Adeli
Khosrow
K
D000284:Administration, Oral; D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism; D001055:Apolipoproteins B / Q000097:blood / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000097:blood; D000071518:Liver X Receptors; D008297:Male; D008647:Mesocricetus; D057093:Orphan Nuclear Receptors; D010766:Phosphorylation; D055550:Protein Stability; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000097:blood; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D064429:Fatty Acid Synthases; D006845:Hydrocarbons, Fluorinated; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008079:Lipoproteins, VLDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D012333:RNA, Messenger; D011972:Receptor, Insulin; D018160:Receptors, Cytoplasmic and Nuclear; D013230:Stearoyl-CoA Desaturase; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D014280:Triglycerides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C106092:microsomal triglyceride transfer protein; C030106:very low density lipoprotein triglyceride