Hepatocyte nuclear factor-1α is an essential regulator of bile acid and plasma cholesterol metabolism

Abstract

Maturity-onset diabetes of the young type 3 (MODY3) is caused by haploinsufficiency of hepatocyte nuclear factor-1alpha (encoded by TCF1). Tcf1-/- mice have type 2 diabetes, dwarfism, renal Fanconi syndrome, hepatic dysfunction and hypercholestrolemia. Here we explore the molecular basis for the hypercholesterolemia using oligonucleotide microchip expression analysis. We demonstrate that Tcf1-/- mice have a defect in bile acid transport, increased bile acid and liver cholesterol synthesis, and impaired HDL metabolism. Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. In intestine and kidneys, Tcf1-/- mice lack expression of the ileal bile acid transporter (Slc10a2), resulting in increased fecal and urinary bile acid excretion. The Tcf1 protein (also known as HNF-1alpha) also regulates transcription of the gene (Nr1h4) encoding the farnesoid X receptor-1 (Fxr-1), thereby leading to reduced expression of small heterodimer partner-1 (Shp-1) and repression of Cyp7a1, the rate-limiting enzyme in the classic bile acid biosynthesis pathway. In addition, hepatocyte bile acid storage protein is absent from Tcf1-/- mice. Increased plasma cholesterol of Tcf1-/- mice resides predominantly in large, buoyant, high-density lipoprotein (HDL) particles. This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifying enzyme lecithin:cholesterol acyl transferase (Lcat). Our studies demonstrate that Tcf1, in addition to being an important regulator of insulin secretion, is an essential transcriptional regulator of bile acid and HDL-cholesterol metabolism.

Bile acid feeding increased proliferative activity and apical bile acid transporter expression in both small and large rat cholangiocytes

“…51 FXR may also regulate ABAT since in the knockout for TCF1 protein (which regu- lates the transcription of the gene encoding FXR1) results in an absence of ABAT in the intestine and kidney. 53 Our studies failed to show in vitro activation of ABAT in small cholangiocytes. It is likely that more chronic exposure to BA is required for BA induction of BAT expression in small cholangiocytes and the mechanisms for de novo activation may involve other pathways other than PKC (possibly involving TCF1/FXR).…”

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

“…Expression of the Asbt gene is under control of hepatocyte nuclear factor HNF1α. Hence, in the HNF1α knockout mouse Asbt expression was undetectable in the ileum at RNA and protein levels (Shih et al 2001). Furthermore, Asbt expression is regulated by bile acids through an activation of the nuclear farnesoid X receptor FXR.…”

A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes

“…However, one promising example of potential translation into clinical practice stems from GWAS reports that common alleles near HNF1A are associated with C-reactive protein (CRP) levels at the population level [2,3]. There was a plausible biological basis for this observation, as the promoter of the CRP gene has two binding sites for hepatocyte nuclear factor 1 alpha (HNF1A), HNF1A is required for CRP expression and the Hnf1a-knockout mouse has reduced Crp expression [4][5][6]. We hypothesised that large-effect, loss-of-function heterozygous HNF1A mutations that are causal for MODY might be associated with more substantial CRP reductions, and we recently confirmed this in a UK study [7].…”