Genetic and molecular effects on hepatocyte nucleocytoplasm protein aggregation

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Protein aggregation occurs in association with a variety of liver diseases and is typically cytoplasmic. A common form of protein aggregates are Mallory-Denk bodies (MDBs) that are found in association steatohepatitis, viral hepatitis and other forms of liver disease. Recent findings indicate that the presence of MDBs provides a poor clinical and histological outcome in patients with hepatitis C. The propensity of form MDBs is linked to the genetic background as supported by higher predisposition to their formation in specific mouse (C57BL > C3H strain) and human (Hispanic > White) genotypes. Among the molecular alterations that positively associate with experimental MDB formation are keratin hypersumoylation and hypoacetylation, which are posttranslational modifications that occur on lysine residues. In addition, there is impaired overall liver sumoylation in C57BL MDB-susceptible strain. Another novel type of protein aggregates are the nuclear lamins that we recently observed in cell culture models and in mouse liver injury models undergoing oxidative stress, and in human chronic liver disease explants. Formation of lamin-containing aggregates is rapid and is noted within days of exposure to the insult, and occurs prior to MDB formation that requires weeks. Lamin aggregation could interfere with one or more nuclear functions, and its rapid onset might serve as an early marker of oxidative injury. Our hypothesis is that genetic variations unmask differences in hepatocyte responses to oxidative injury which manifest as nuclear and cytoplasmic protein aggregation. This hypothesis will be tested using 4 specific aims: (i) Use expression profiling to compare underlying genetic differences in male and female livers from C3H and C57BL mouse strains; (ii) Characterize the cell fate of MDB-containing hepatocytes in mouse models and patients with alcohol-related liver disease; (iii) Characterize keratin acetylation, and its relationship to keratin sumoylation and aggregation, during oxidative stress; and (iv) Define the biochemical and functional alterations that associate with nuclear lamin disorganization in response to liver injury. Completion of our aims should provide fundamental knowledge regarding genetic modifiers and posttranslational regulation that associate with MDB formation, and the consequence of MDB formation at the level of the individual hepatocyte. Furthermore, the hitherto unappreciated aggregation of nuclear lamins might provide a new mechanism for how liver injury proceeds, with consequent potential therapeutic and diagnostic targets and approaches.