Identification of Novel Pathways That Control Farnesoid X Receptor-mediated Hypocholesterolemia

Abstract

Farnesoid X receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized Fxr ؊/؊ mice and mice deficient in scavenger receptor class B type I (SR-BI), together with an FXR-specific agonist and adenovirus expressing hepatocyte nuclear factor 4␣ or constitutively active FXR, to identify the mechanisms by which activation of FXR results in hypocholesterolemia. We identify a novel pathway linking FXR to changes in hepatic p-JNK, hepatocyte nuclear factor 4␣, and finally SR-BI. Importantly, we demonstrate that the FXR-dependent increase in SR-BI results in both hypocholesterolemia and an increase in reverse cholesterol transport, a process involving the transport of cholesterol from peripheral macrophages to the liver for excretion into the feces.In addition, we demonstrate that FXR activation also induces an SR-BI-independent increase in reverse cholesterol transport and reduces intestinal cholesterol absorption. Together, these data indicate that FXR is a promising therapeutic target for treatment of hypercholesterolemia and coronary heart disease.

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

“…It is therefore most conceivable that reduction of plasma cholesterol upon PX treatment in mice that do express hepatic FXR is due to suppressed transcription of apolipoprotein A-I 36 and enhanced expression of scavenger receptor class B-I (SCARB1/SR-BI) upon FXR activation, as reported previously by others. 37 In keeping with this hypothesis, we found upregulation of hepatic SR-BI mRNA as well as protein (data not shown). Thus, de novo cholesterol synthesis by the liver, as supported by a profound upregulation of Hmcgr expression and direct quantification of cholesterol synthesis using mass isotopomer distribution analysis, apparently compensates for the increased loss of cholesterol by M A N U S C R I P T…”

Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters

“…3B, C). Increased expression of HNF4 by FXR agonist, GW4064, was reported as a causal factor for FXR-mediated elevation of SR-BI expression in mice (35). However, in our study, HNF4 protein levels were unchanged in these samples, which were in line with the negative results of qRT-PCR.…”

“…One study reported that FXR activation by synthetic agonist GW4064 increased transcription factor HNF4 protein levels that led to the transcriptional activation of SR-BI gene through HNF4 binding sequences embedded in the promoter region and intronic sequences of murine SR-BI gene (35). Another study identified multiple functional FXR binding sites (IR1) in the first intron of the murine SR-BI gene (47).…”

“…However, in our study, HNF4 protein levels were unchanged in these samples, which were in line with the negative results of qRT-PCR. It was shown that activation of Janus N-terminal kinase (p-JNK) by GW4064 was responsible for increased HNF4 expression and subsequent SR-BI upregulation by this FXR ligand in mice (35). Thus, we examined p-JNK and total JNK protein levels in hamster livers and we did not detect differences between OCA-treated and control groups (supplemental Fig.…”

Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

“…Hepatic LDL receptor (LDLR) expression is not different, but the production of TG-rich, apoB-containing lipoproteins as well as intestinal cholesterol absorption are increased, probably causing the elevated non-HDL-C levels upon FXR defi ciency ( 27 ). In the same line, FXR activation in mice with a synthetic FXR agonist reduces intestinal cholesterol absorption by 50% ( 30 ). The authors propose a reduction in BA pool size and hydrophobicity index (due to an increased tauro-␤ -MCA/TCA ratio) upon FXR activation ( 31 ) as underlying mechanism, as a reduced BA pool hydrophobicity has been associated with a decrease in cholesterol absorption ( 32 ).…”