Bioenergetics: Open Access

FXR activation by obeticholic acid induces hepatic SR-BI gene expression through a novel mechanism of transcriptional synergy with the nuclear receptor LXR

3^rd International Conference on Lipid Science and Technology

December 11-12, 2017 | Rome, Italy

Jingwen Liu

Veterans Affairs Palo Alto Health Care System, USA

Scientific Tracks Abstracts: Bioenergetics

Abstract:

The farnesoid X receptor (FXR) and liver X receptor (LXR) are known to regulate distinct biological pathways in BA synthesis and cholesterol metabolism. Obeticholic acid (OCA) is an FXR agonist being developed for treating various chronic liver diseases. Previous studies reported inconsistent effects of OCA on regulating plasma cholesterol levels in different animal models and in different patient populations. The mechanisms underlying its divergent effects yet have not been thoroughly investigated. The scavenger receptor class B type I (SR-BI) is an FXR modulated gene and the major receptor for HDL-C. We recently showed that OCA treatment effectively lowered plasma HDL-C levels and increased hepatic SR-BI expression in hypercholesterolemic hamsters but not in normolipidemic hamsters, suggesting that hepatic cholesterol might play a role in OCA-induced SR-BI transcription. In this current study, by conducting genomic sequence analysis, reporter assays and direct DNA binding assays, we have identified a highly conserved regulatory region in the first intron of hamster SR-BI gene that contains a functional FXRE motif and an LXRE site separated by 57 base pairs. Promoter reporter activity assays demonstrated the functional involvement of this critical regulatory region in SR-BI gene transcription upon activations of FXR and LXR in a synergistic fashion. In vivo studies of normolipidemic hamsters showed that hepatic SR-BI gene expression is not affected by separate treatment of OCA or LXR agonist GW3965 but the co-activation of FXR and LXR by the combined treatment of OCA and GW3965 results in significant increases in hepatic SR-BI mRNA and protein levels. Taken together, we have discovered an unprecedented cross-talk between FXR and LXR that leads to a synergistic activation of SR-BI gene transcription in liver tissue and consequently affected HDL-C metabolism. Our novel findings shed new light for a better understanding of lipid regulatory effects of OCA in hyperlipidemic patients. Recent Publications: 1. Dong B, Young M, Liu X, Singh A B and Liu J (2017) Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters. Journal of Lipid Research 58(2):350â??363. 2. Singh A B and Liu J (2017) Identification of hepatic lysophosphotidylcholine acyltransferase 3 as a novel target gene regulated by peroxisome proliferator-activated receptor δ. Journal of Biological Chemistry 292(3):884â??897. 3. Singh A B, Kan C F, Dong B and Liu J (2016) SREBP2 activation induces hepatic long-chain acyl-CoA synthetase 1 expression in vivo and in vitro through a SRE motif of ACSL1 C-promoter. Journal of Biological Chemistry 291(10):5373-5384. 4. Shende V, Wu M, Singh A B, Dong B, Kan CF and Liu J (2015) Reduction of circulating PCSK9 and LDL-C levels by liver-specific knockdown of HNF1α in normolipidemic mice. Journal of Lipid Research 56(4):801â??809. 5. Dong B, Singh A B, Azhar S, Seidah N G and Liu J (2015) High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels. Atherosclerosis 239(2):364-374.

Biography :

Jingwen Liu is a Principal Investigator at the Palo Alto VA Hospital where she directs a research program seeking new therapeutic options to treat cardiometabolic diseases through studies conducted in liver cells and various animal models. Among numerous accomplishments, her team has characterized a new cellular pathway that upregulates the liver LDL receptor transcription through a cholesterol-independent mechanism and identified a novel post-transcriptional mechanism of LDLR gene that mediates the cholesterol-lowering effects of herbal medicine berberine. In the last decade, PCSK9 has emerged as a new therapeutic target for treating hypercholesterolemia. Her research in characterizing the transcriptional mechanism of PCSK9 has brought new insight for developing novel therapeutic approach to inhibit PCSK9 biosynthesis with a potential to improve the efficacy of current cholesterol-lowering drug statins. Her recent study in obeticholic acid has led to new understandings of lipid regulatory effects of FXR agonists in hyperlipidemic patients.