Liver X receptor alpha (LXR alpha) is considered a master regulator of hepatic lipid metabolism, however, little is known about the link between LXR activation, hepatic insulin signaling, and VLDL-apolipoprotein B (apoB) assembly and secretion. Here, we examined the effect of LXR alpha activation on hepatic insulin signaling and apoB-lipoprotein production. In vivo activation of LXR alpha for 7 days using a synthetic LXR agonist, TO901317, in hamsters led to increased plasma triglyceride (TG; 3.6-fold compared to vehicle-treated controls, p=0.006), apoB (54%, p<0.0001), and very low density lipoprotein (VLDL)-TG (8-fold increase compared to 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 Co-A 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. MTP mRNA and protein were unchanged, however, likely due to 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) 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 two-fold increase in IRS-2 mass (228%, p=0.0037), and a 3-fold increase in IRS-2 tyrosine phosphorylation (321%, p=0.012) was 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.