MITOCHONDRIAL ABNORMALITIES IN NAFL ? NONALCOHOLIC FATTY LIVER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mitochondrial dysfunction appears to play a key role in fatty liver. This form of liver disease (commonly referred to as NASH or NAFL) is reaching epidemic proportions due to the increasing prevalence of obesity and diabetes. Functionally, the fatty liver has diminished ATP in vitro by biochemical tests and in vivo by MR Spec, decreased expression of ETC complexes, increased expression of uncoupling protein, and apoptosis is increased in these livers. Morphologically, by TEM the mitochondria are commonly swollen and contain crystalline inclusions which appear to be in continuity with the cristae suggesting a conformational change. Their resemblance to plant etioplasts further suggest a common origin in abnormal formation of a lipid bilayer. The presence of these forms correlates to indices of lipid peroxidation but not to the degree of light microscopic injury suggesting that these may serve as an adaptive mechanism to oxidative stress. Three-dimensional EM imaging may provide additional clues to the origin of these structures and this may provide better understanding of the pathogenesis of NAFL and its optimal therapy. There may also be implications for associated neurodegenerative diseases and hepatocellular cancer which commonly contains areas of steatosis. It is my intention to use this data to apply for NIH and other sources for additional funding.