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

Abstract

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 ϭ 0.006), apoB (54%, P Ͻ 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)␤ subunit mass (39%, P ϭ 0.014) and insulin receptor substrate (IRS)-1 tyrosine phosphorylation (24%, P ϭ 0.023), as well as increases in protein tyrosine phosphatase (PTP)1B (29%, P Ͻ 0.001) protein mass. In contrast to IRS-1, a twofold increase in IRS-2 mass (228%, P ϭ 0.0037) and a threefold increase in IRS-2 tyrosine phosphorylation (321%, P ϭ 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 NUCLEAR LIVER X RECEPTORS (LXRs) act as intracellular sensors for sterols (22) and, in response to ligands, induce transcriptional responses to maintain cholesterol, lipid, and glucose homeostasis (23,25,51). LXR is a central player in energy homeostasis, as indicated by its putative involvement in lipogenesis, gluconeogenesis, lipoprotein metabolism, and glucose uptake (46). The initial rationale for studies of LXR and LXR agonists was based on observations of their beneficial effects on reverse cholesterol transport, a process whereby cholesterol is transported from extrahepatic tissues to the liver for eventual excretion through the bile (9). Synthetic LXR agonists have therefore been designed with the intention of treating disorders such as atherosclerosis and diabetes (8, 17).The two isoforms of LXR, ␣ and ␤, are highly homologous and form obligate heterodimers with retinoid X receptor (RXR) (11,55). LXR is part of a large family of ligand-activated nuclear transcription factors that includes the farnesoid X receptor (FXR). Hepatic lipogenic genes known to b...

Liver X receptor activation promotes macrophage-to-feces reverse cholesterol transport in a dyslipidemic hamster model

“…One might also speculate that the 0.3% cholesterol might increase LDL-cholesterol levels through a lower hepatic LDL-receptor expression, because LXR has been shown to induce the E3 ubiquitin ligase Inducible Degrader of the LDLR in mice ( 26 ). Interestingly, treatment with the LXR agonist TO901317 in hamster disregulates hepatic insulin signaling, which dramatically leads to higher triglyceride-rich VLDL particles production ( 27 ). The present data suggest that similar effects may have occurred in our hamster model.…”

Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver

“…Attenuation of LXR-␣ signaling may also account for the changes in the expression of several genes: SREBP-1c, Cyp7A1, ABCA1, ABCG5, ABCG8 ( 20 ), SR-BI ( 21 ), and apoB ( 22 ). In addition to the reduced expression of LXR-␣ ( Fig.…”

“…It is also noteworthy that expressions of many of LXR-␣ target genes were decreased as discussed before. Because LXR-␣ activity is a key determinant of VLDL production ( 22 ), it is reasonable to speculate that ablation of Supplemental Material can be found at:…”

Serum TG-lowering properties of plant sterols and stanols are associated with decreased hepatic VLDL secretion

“…LXRA (NR1H3) is a transcription factor involved in lipid metabolism and is an intracellular sensor for sterols ( 34 ). According to Basciano et al ( 35 ) , activation of LXR leads to increased plasma triglycerides and VLDL. In our study, we observed opposite effects; i.e., decreased plasma TG and VLDL production in combination with downregulation of hepatic LXR target genes after supplementation of plant sterols and stanols to HFD.…”