The Role Mitochondrial Dysfunction in Non-Alcoholic Fatty Liver Disease
The aims of this proposal will be addressed via separate isotopic studies occurring at different time points during a prolonged fast. in subjects with naFLD, these studies will be carried out before and after treatment with Vitamin e or placebo. The study is designed to harness the physiologic changes that occur with short- and long-term fasting to provide a rapid and cost-effective method to accomplish the aims of the application. aims 1 and 2 will be addressed under the umbrella of a total of 20 control subjects, 20 subjects with bland steatosis, and 20 subjects with naSH that will be recruited for study. We anticipate a dropout rate of approximately 20%, so target enrollment will be set at 75 to account for attrition and screen failures. Subjects with naSH will be matched to those with bland steatosis based upon age, ethnicity, BMi, and insulin sensitivity (insulin clamp). all subjects with hepatic steatosis will undergo liver biopsy as part of the study, with naFLD activity Score determined by an experienced hepatopathologist. a repeat biopsy will also be performed in naFLD subjects after receiving randomized vitamin e or placebo therapy. The study will span approximately 18 weeks. This approach alleviates the need to have separate methodologically based protocols, thereby limiting the number of subjects required to address the central hypotheses of the application and simultaneously maximizing the use of university resources and niH monies. Furthermore, subjects with bland steatosis and naSH who complete the overnight fast to address the first two aims of the application will be immediately utilized to address aim 3 of the proposal. importantly, the results of aim 3 are not dependent on the outcomes of studies addressing the first two aims: while aims 1 and 2 rely on a separate control group composed of lean, healthy subjects to determine how mitochondrial function is altered in naFLD, the determination of the effect of vitamin e on mitochondrial function will be accomplished by having each naFLD subject serve as their own control. as a result, resources and monies used to accomplish aims 1 and 2, regardless of outcomes, can be viewed as an investment in aim 3 via the provision of well-phenotyped subjects. The temporal relationship between the studies proposed to address each aim also ensures a rapid evaluation of all the hypotheses of the proposal, limited only by the rate of subject enrollment and duration of study.
1. Male and Female, Age 18-65 years of all racial and ethnic origins
2. Hepatic steatosis by radiologic study with or without ALT elevation
3. BMI < 35 kg/m2
4. English language
5. Females of childbearing potential must be willing to practice an acceptable form of birth control throughout the protocol.
1. Age 18-65 years.
2. BMI > 20 and < 25 kg/m2