This proposal describes a 5 year training program for the development of an academic career in Hepatology, oriented to basic science research. The principal investigator has scientific background on Wilson Disease and now will expand upon her scientific skills through a unique integration of resources. This program will promote the understanding of the molecular mechanisms relating copper overload to steatosis in Wilson Disease, with the ultimate objective to explore new therapies for this rare disease based on the modification of these aberrant underlying processes. Dr. CH Halsted and Dr. JC Rutledge will mentor the principal investigator's scientific and career development. They are recognized leaders in the fields of methionine and lipid metabolism and they have trained numerous postdoctoral fellows and graduate students. The research will focus on the inhibitory effect exerted by copper accumulation on the enzyme S-adenosylhomocysteine (SAH) hydrolase. Preliminary data demonstrate that SAH hydrolase inhibition is followed by significant reduction of the hepatic S-adenosylmethionine (SAM):SAH ratio, a marker of methylation status, and later time-dependent homocysteine increase. The proposed experiments will entail the use of a copper chelator to reduce hepatic copper concentration and improve SAH hydrolase activity, thereby demonstrating the direct effect of copper on this enzyme, and further inhibition of SAH hydrolase both in vivo (with DZA) and in vitro (with shRNA carried by lentivirus) and provision of methyl groups as supplemental betaine, a compound known to correct aberrant methionine metabolism. An assortment of biochemical, molecular, and cellular techniques, including epigenetic methods will be used to study methionine and lipid metabolism.
The specific aims i nclude: 1) Establishing relationships among copper accumulation, hepatic steatosis, and aberrant methionine metabolism, 2) Determining if the methyl donor betaine can improve lipid metabolism in tx-j mice and in primary hepatocytes from the same animal model, and 3) Determining if steatosis in Wilson disease is mediated by epigenetic regulation of expressions of genes relevant to lipid synthesis. This will be the first detailed analysis of the mechanisms of hepatic steatosis based on the metabolism of methionine in this rare disease. The University of California Davis provides an ideal setting for training physician- scientists by incorporating expertise from diverse resources into customized programs. Such an environment maximizes the potential for the principal investigator to establish a scientific niche from which an academic career can be constructed. The successful outcome of the proposed experiments will promote an understanding of the metabolic processes underlying the pathogenesis of steatosis in Wilson disease, an orphan disease (included in the NIDDK action plan for Liver Disease Research) whose genetic background is well-established but whose metabolic etiopathogenesis is unclear. The study will also provide insights into the role of copper and methionine metabolism in more common diseases, such as non-alcoholic fatty liver disease.

Public Health Relevance

Wilson disease, an autosomic recessive disorder due to hepatic copper excess, is frequently characterized by fat accumulation in the liver. We will study the interaction between copper and hepatic methionine metabolism with the ultimate objective to explore new therapies based on modification of these underlying processes. The study will also provide insights into the role of copper and methionine metabolism in more common diseases, such as non-alcoholic fatty liver disease.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK084111-05
Application #
8666742
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Podskalny, Judith M,
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Davis
State
CA
Country
United States
Zip Code
95618
Le, Anh; Shibata, Noreene M; French, Samuel W et al. (2014) Characterization of timed changes in hepatic copper concentrations, methionine metabolism, gene expression, and global DNA methylation in the Jackson toxic milk mouse model of Wilson disease. Int J Mol Sci 15:8004-23
Medici, Valentina; Schroeder, Diane I; Woods, Rima et al. (2014) Methylation and gene expression responses to ethanol feeding and betaine supplementation in the cystathionine beta synthase-deficient mouse. Alcohol Clin Exp Res 38:1540-9
Medici, Valentina; Shibata, Noreene M; Kharbanda, Kusum K et al. (2014) Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease. Epigenetics 9:286-96
Medici, Valentina; Halsted, Charles H (2013) Folate, alcohol, and liver disease. Mol Nutr Food Res 57:596-606
Medici, Valentina; Shibata, Noreene M; Kharbanda, Kusum K et al. (2013) Wilson's disease: changes in methionine metabolism and inflammation affect global DNA methylation in early liver disease. Hepatology 57:555-65