Stimulation of Lipogenesis by Pharmacological Activation of the Liver X Receptor Leads to Production of Large, Triglyceride-rich Very Low Density Lipoprotein Particles

Abstract

The oxysterol-activated liver X receptor (LXR) provides a link between sterol and fatty acid metabolism; activation of LXR induces transcription of lipogenic genes. This study shows that induction of the lipogenic genes Srebp-1c, Fas, and Acc1 upon administration of the synthetic LXR agonist T0901317 to C57BL/6J mice (10 mg/kg/day, 4 days) is associated with massive hepatic steatosis along the entire liver lobule and a 2.5-fold increase in very low density lipoprotein-triglyceride (VLDL-TG) secretion. The increased VLDL-TG secretion was fully accounted for by formation of larger (129 ؎ 9 nm versus 94 ؎ 12 nm, a 2.5-fold increase of particle volume) TG-rich particles. Stimulation of VLDL-TG secretion did not lead to elevated plasma TG levels in C57BL/6J mice, indicating efficient particle metabolism and clearance. However, T0901317 treatment did lead to severe hypertriglyceridemia in mouse models of defective TG-rich lipoprotein clearance, i.e. APOE*3-Leiden transgenic mice (3.2-fold increase) and apoE؊/؊ LDLr؊/؊ double knockouts (12-fold increase). Incubation of rat hepatoma McA-RH7777 cells with T0901317 also resulted in intracellular TG accumulation and enhanced TG secretion. We conclude that, in addition to raising high density lipoprotein cholesterol concentrations, pharmacological LXR activation in mice leads to development of hepatic steatosis and secretion of atherogenic, large TG-rich VLDL particles.

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor‐driven transcription of hepatic lipogenic genes in vivo

“…As expected based on the observations of Grefhorst et al . (2002) and Chisholm et al . (2003), the T0901317 and palm oil treatment resulted in an increased liver weight as compared with the DMSO control group (Figure 4A).…”

“…(2002). The mice received palm oil to further induce hepatic steatosis and ensure optimal stimulation of PRMT3 translocation to the nucleus (Chisholm et al ., 2003; Go et al ., 2015; Kim et al ., 2015a).…”

“…These values were similar to the plasma lipid levels of T0901317‐treated mice described by Grefhorst et al . (2002). Subsequent treatment with SGC707 did not affect plasma cholesterol levels at the dose of 10 mg·kg −1 , while the group treated with 30 mg·kg −1 SGC707 showed an additional significant increase in cholesteryl esters (1.9‐fold increase) and free cholesterol levels (2.3‐fold increase) as compared with the T0901317 + palm oil‐treated group (Figure 1A and B).…”

“…Group size was determined based on the paper by Grefhorst et al . (2002) showing that n  = 4 per group was the minimum number of mice to show effects on gene expression (our primary readout). Since the SGC707 compound has not been used in this context before, we slightly increased the group size while maintaining minimal amounts of mice needed.…”

“…However, the LXR also regulates de novo hepatic lipogenesis via activation of the transcription factor sterol regulatory element‐binding protein 1c (SREBP1c) and direct interaction with hepatic lipogenic genes (Joseph et al ., 2002a; Talukdar and Hillgartner, 2006; Cha and Repa, 2007). As a result, LXR activation by the use of LXR agonists leads to unwanted hepatic steatosis (Schultz et al ., 2000; Grefhorst et al ., 2002). This steatotic effect of LXR agonism has hampered the development of LXR agonists for clinical use in humans.…”