Our understanding of the molecular determinants of bile formation and cholestasis has been greatly enhanced over the past few years as direct consequence of the cloning of hepatobiliary transporter genes. Recent findings indicate that reductions in the expression of transporter genes can lead to cholestasis, and that the underlying mechanisms involve specific down-regulation of transcription. The overall objectives of this proposal are to define the humoral mediators and molecular pathways that transcriptionally regulate hepatobiliary transporter genes. Initial studies will concentrate on expanding our ongoing work on the regulation of one of the best characterized hepatobiliary transporter genes, the basolateral Na+-dependent bile acid co-transporter, ntcp, in order to provide a focused framework to explore the regulation of other critical genes involved in bile formation.
Aim 1. Determine the cellular and molecular contributions leading to endotoxin-induced down-regulation of the ntcp gene.
Aim 2. Determine the molecular signaling pathways and nuclear transactivators that regulate the ntcp gene promoter.
Aim 3. Determine if bile acids themselves regulate the ntcp gene promoter.
Aim 4. Investigate common regulatory pathways of hepatobiliary transporter genes. The limited availability of effective agents to treat cholestatic diseases detailed explorations into avenues of research that could impact upon the design and use of novel therapeutics. Long-range goals include the potential translation of these studies into the development of transcriptionally active compounds (e.g., bile acids or nuclear hormone receptor ligands) adapted towards ameliorating the pathogenesis of cholestasis.
|Sultan, Mutaz; Rao, Anuradha; Elpeleg, Orly et al. (2018) Organic solute transporter-? (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis. Hepatology 68:590-598|
|Arab, Juan P; Karpen, Saul J; Dawson, Paul A et al. (2017) Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology 65:350-362|
|Kosters, Astrid; Abebe, Demesew F; Felix, Julio C et al. (2016) Inflammation-associated upregulation of the sulfated steroid transporter Slc10a6 in mouse liver and macrophage cell lines. Hepatol Res 46:794-803|
|Rao, Anuradha; Kosters, Astrid; Mells, Jamie E et al. (2016) Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice. Sci Transl Med 8:357ra122|
|Dawson, Paul A; Karpen, Saul J (2015) Intestinal transport and metabolism of bile acids. J Lipid Res 56:1085-99|
|Karpen, Saul J; Dawson, Paul A (2015) Not all (bile acids) who wander are lost: the first report of a patient with an isolated NTCP defect. Hepatology 61:24-7|
|Desai, Moreshwar S; Eblimit, Zeena; Thevananther, Sundararajah et al. (2015) Cardiomyopathy reverses with recovery of liver injury, cholestasis and cholanemia in mouse model of biliary fibrosis. Liver Int 35:1464-77|
|Dawson, Paul A; Karpen, Saul J (2014) Bile acids reach out to the spinal cord: new insights to the pathogenesis of itch and analgesia in cholestatic liver disease. Hepatology 59:1638-41|
|Kosters, Astrid; Felix, Julio C; Desai, Moreshwar S et al. (2014) Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXR? variant lacking the DNA-binding domain. J Hepatol 60:362-9|
|El Kasmi, Karim C; Anderson, Aimee L; Devereaux, Michael W et al. (2013) Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med 5:206ra137|
Showing the most recent 10 out of 32 publications