Abstract 60: The ABCG5 ABCG8 Sterol Transporter Opposes Insulin Resistance and Fatty Liver Disease Independent of Phytosterol Accumulation

ABCG5 and ABCG8 form a complex (G5G8) that opposes the absorption of plant sterols, but is also expressed in liver where it promotes the excretion of cholesterol into bile. Hepatic G5G8 is transcriptionally regulated by a number of factors implicated in the development of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Therefore, we hypothesized that G5G8 may influence the development of diet-induced obesity phenotypes independently of its role in opposing phytosterol absorption. G5G8 knockout (KO) mice and their wild type (WT) littermates were challenged with plant sterol free low fat (LF) or high fat (HF) diets. Weight gain and the rise in fasting glucose were accelerated in G5G8 KO mice following HF feeding. HF-fed G5G8 KO mice had increased liver weight, hepatic lipids and plasma ALT compared to WT controls. Consistent with the development of NAFLD, macrophage infiltration, the number of TUNEL positive cells and the expression of proinflammatory cytokines were also increased in G5G8 KO mice, but there was no evidence of fibrosis. Hepatic lipid accumulation was associated with increased mRNA levels for PPARγ and PPARγ target genes, but not genes involved in lipogenesis. Phosphorylation of eukaryotic translation initiation factor 2α (eiF2α) and expression activating transcription factor 4 (ATF4) and tribbles 3 (Trb3) were elevated in HF-fed G5G8 KO mice, a pathway that links the unfolded protein response (UPR) to the development if insulin resistance through inhibition of protein kinase B (Akt) phosphorylation. However, the remaining components of the UPR were unchanged. Conclusion: G5G8 plays a previously unappreciated role in the development of insulin resistance and fatty liver disease by opposing hepatic accumulation of cholesterol and phosphorylation of eiF2α.