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

Maturity-onset diabetes of the young type 3 (MODY3) is caused by haploinsuf ficiency of hepatocyte nuclear factor-let (encoded by TCF1). Tcf1(-/-) mice have type 2 diabetes, dwarfism, renal Fanconi syndrome, hepatic dysfunctio n and hypercholestrolemia. Here we explore the molecular basis for the hype rcholesterolemia using oligonucleotide microchip expression analysis. We de monstrate that Tcf1(-/-) mice have a defect in bile acid transport, increas ed bile acid and liver cholesterol synthesis, and impaired HDL metabolism. Tcf1(-/-) liver has decreased expression of the basolateral membrane bile a cid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal b ile acid uptake and elevated plasma bile acid concentrations. In intestine and kidneys, Tcf1(-/-) mice lack expression of the ileal bile acid transpor ter (Slc10a2), resulting in increased fecal and urinary bile acid excretion . The Tcf1 protein (also known as HNF-1 alpha) 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 re pression of Cyp7a1, the rate-limiting enzyme in the classic bile acid biosy nthesis pathway. In addition, hepatocyte bile acid storage protein is absen t from Tcf1(-/-) mice. Increased plasma cholesterol of Tcf1(-/-) mice resid es predominantly in large, buoyant, high-density lipoprotein (HDL) particle s. This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifyi ng enzyme lecithin:cholesterol acyl transferase (Lcat). Our studies demonst rate that Tcf1, in addition to being an important regulator of insulin secr etion, is an essential transcriptional regulator of bile acid and HDL-chole sterol metabolism.