Research Interests

Hormone signaling and liver pathology; bile acids; anticancer agents and their side effects; tumor formation and drug responsiveness

Research Program

Chronic liver disease and cirrhosis in particular, is the 12th leading cause of mortality in the United States and the 4th leading cause of death for individuals aged 45 to 54 years. The prognosis is poor, generally irreversible, and marked by progressive destruction of the liver cells. Around 50% of patients with liver disease and 80% of cirrhotic patients display glucose intolerance associated with a decreased gluconeogenic response to glucagon. This decreased glucagon-induced hepatocellular glucose production is due to a significant hepatic resistance to glucagon and attenuation of glucagon-induced cAMP production. Our early studies showed glucagon responsiveness to be significantly attenuated in hepatocytes isolated from cholestatic hamsters, and this effect was mimicked by submicellar concentrations of bile acids including chenodeoxycholic acid (CDCA) in hepatocytes isolated from control hamsters. Our data suggested the attenuated cAMP response induced by bile acids to be PKCalpha and/or PKCdelta-mediated. Our overarching hypothesis is that in hepatocytes, phosphorylation of PKC by CDCA leads to activation of this kinase, which in turn phosphorylates the glucagon receptor and attenuates glucagon responsiveness, which is one of the events associated to the progression of liver disease during cholestasis. These studies will define molecular mechanisms regulating both PKC and glucagon receptor activation by bile acids. Furthermore, the delineation of the molecular balance between phosphorylation and activation of PKC may have the added benefit of identifying novel molecular targets for rational drug design in the treatment of cholestatic hepatobiliary disorders, as well as diabetes. Public Health Relevance: This study will highlight novel mechanisms by which physiological control of signal transduction is attenuated in cholestasis. The knowledge gained from these studies could in turn impact both the diagnosis and treatment of cholestatic hepatobiliary disorders, as well as diabetes.

Selected Publications

• Miyazaki T, Doy M, Unno R, Honda A, Ikegami T, Itoh S, Bouscarel B and Matsuzaki Y. Regulatory T cells and liver pathology in a murine graft versus host response model. Hepatol Res 39:585-594, 2009.
• Miyazaki T, Bouscarel B, Ikegami T, Honda A, Matsusaki Y. The Protective effect of taurine against hepatic damage in a model of liver disease and hepatic stellate cells. Adv Exp Med Biol. 643:585-94, 2009.
• Krilov L, Nguyen A, Miyazaki T, Unson CG, Bouscarel B. Glucagon receptor recycling: role of carboxyl terminus, {beta}-arrestins, and cytoskeleton. Am J Physiol Cell Physiol 295:C1230-C1237, 2008.
• Le M, Krilov L, Meng J, Chapin-Kennedy K, Ceryak S, Bouscarel B. Bile acids stimulate PKC{alpha} autophosphorylation and activation: role in the attenuation of prostaglandin E1-induced cAMP production in human dermal fibroblasts. Am J Physiol Gastrointest Liver Physiol 291:G275-G287, 2006.
• Zhang Y, Ikegami T, Honda A, Miyazaki T, Bouscarel B, Rojkind M, Hyodo I and Matsuzaki Y. Involvement of integrin-linked kinase in carbon tetrachloride-induced hepatic fibrosis in rats. Hepatology 44:612-622, 2006.
• Ikegami T, Krilov L, Meng J, Patel B, Chapin-Kennedy K, Bouscarel B. Decreased glucagon responsiveness by bile acids: a role for protein kinase Calpha and glucagon receptor phosphorylation. Endocrinology 147: 5294-5302, 2006.