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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.

Biliary atresia (BA) is the end result of a destructive, rhosis. Until recently, BA was uniformly fatal; liver inflammatory process that affects intra-and extrahe-transplantation has altered the inevitability of that patic bile ducts, leading to fibrosis and obliteration of outcome, but at a ''cost'' to the patient, who must face the biliary tract with the development of biliary cirrho-the consequences of living with a transplanted organ, sis. It is the commonest cause of chronic cholestasis in and to society in real dollars. Our understanding of the infants and children, and therefore is the most frequent etiology and pathogenesis of BA has remained virtually indication for liver transplantation in this age group. unchanged for two decades. This disorder is of interest The disease occurs worldwide, affecting an estimated 1 to all individuals involved in basic and clinical studies basis for BA; 2) the optimal timely and precise methods of discrimination from other causes of neonatal cholestasis; 3) the natural history of BA; 4) the optimal use Biliary atresia (BA), the most serious digestive disand timing of medical and surgical interventions (porease affecting infants, is an idiopathic, localized, comtoenterostomy and transplantation); and 5) the effect plete obliteration or discontinuity of the hepatic or comof preexisting liver disease or surgical complications mon bile ducts at any point from the porta hepatis (cholangitis, sepsis, peritonitis) on the outcome of to the duodenum. 1,2 Obstruction of bile flow leads to transplantation. Because a small number of patients cholestasis, progressive fibrosis, and, ultimately, cirare seen in individual centers and patients are not managed in a uniform manner between centers, an accurate assessment of these issues is difficult. ThereAbbreviations: BA, biliary atresia; HPE, hepatoportoenterostomy; BASE, fore, a collaborative, multicenter study is needed; a hybiliary atresia splenic malformation syndrome; CDC, chenodeoxycholic acid;pothesis potentially subject to study in such a project CMV, cytomegalovirus. is that BA is the phenotype of several underlying disor- nature of the disorder has perplexed physicians for over Cincinnati,

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