The liver plays a central role in the complex process of cholesterol homeostasis. Hepatic conversion of cholesterol to bile acids is a particularly important aspect of this process that is tightly regulated by nuclear hormone receptors. In response to an increased cholesterol load, activation of the LXRs increases bile acid production. Conversely, activation of the bile acid sensor FXR by increased bile acid levels decreases bile acid production via a nuclear receptor cascade that also includes the orphan receptors SHP and LRH-1. In addition to this repression of bile acid biosynthetic enzymes, FXR regulates expression of genes involved in bile acid transport and lipoprotein metabolism. The identification of FXR as a key regulator of cholesterol metabolism raises the important question of how exogenous FXR ligands might affect cholesterol levels. We have identified guggulsterone, the active component of a natural extract that lowers LDL cholesterol in humans, as an FXR antagonist. Strong evidence that inhibition of FXR is responsible for the cholesterol lowering effect of guggulsterone is provided by the observation that mice lacking FXR are resistant to this effect. We have also identified cafestol, a coffee oil and the most potent LDL cholesterol raising agent known, as a potential FXR agonist. We hypothesize that FXR antagonists provide a novel therapeutic approach to decreasing cholesterol levels. To test this hypothesis and further explore the function of FXR we will: 1) define the specific and overlapping functions of FXR isoforms, particularly their expression patterns and functional effects on different promoters, 2) use wild type and FXR knockout mice to test the role of FXR in the effects of guggulsterone and cafestol, and 3) define the molecular and biochemical basis for the effects of guggulsterone on cholesterol metabolism in vivo. These studies will provide new insights into the molecular basis of FXR function and its potential as a therapeutic target for modulation of cholesterol metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Endocrinology Study Section (END)
Program Officer
Margolis, Ronald N
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Jung, Dongju; York, J Philippe; Wang, Li et al. (2014) FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway. Pflugers Arch 466:1011-9
Xia, Xuefeng; Jung, Dongju; Webb, Paul et al. (2012) Liver X receptor ýý and peroxisome proliferator-activated receptor ýý regulate cholesterol transport in murine cholangiocytes. Hepatology 56:2288-96
Zhang, Lisheng; Huang, Xiongfei; Meng, Zhipeng et al. (2009) Significance and mechanism of CYP7a1 gene regulation during the acute phase of liver regeneration. Mol Endocrinol 23:137-45
Li, Yilan; Ross-Viola, Jennifer S; Shay, Neil F et al. (2009) Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. J Nutr 139:898-904
Del Bas, Josep Maria; Ricketts, Marie-Louise; Vaqué, Montserrat et al. (2009) Dietary procyanidins enhance transcriptional activity of bile acid-activated FXR in vitro and reduce triglyceridemia in vivo in a FXR-dependent manner. Mol Nutr Food Res 53:805-14
Ricketts, Marie-Louise; Boekschoten, Mark V; Kreeft, Arja J et al. (2007) The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors. Mol Endocrinol 21:1603-16
Yang, Fan; Huang, Xiongfei; Yi, Tangsheng et al. (2007) Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. Cancer Res 67:863-7
Wang, Li; Huang, Jiansheng; Saha, Pradip et al. (2006) Orphan receptor small heterodimer partner is an important mediator of glucose homeostasis. Mol Endocrinol 20:2671-81
Ma, Ke; Saha, Pradip K; Chan, Lawrence et al. (2006) Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 116:1102-9
Huang, Wendong; Ma, Ke; Zhang, Jun et al. (2006) Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312:233-6

Showing the most recent 10 out of 17 publications