NONALCOHOLIC STEATOHEPATITIS (NASH): IS LEPTIN AN ETIOLOGICAL FACTOR (PHASE2)

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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. Nonalcoholic steatohepatitis (or NASH) is known to be caused by deposition of fat in the liver and development of scarring as a consequence of fat deposition. This condition occurs more frequently in overweight and obese persons. It is often associated with resistance to the actions of insulin hormone, the primary hormone regulating blood sugar in the body. Fat cells secrete a hormone called leptin. In recent years, we have learned that obese or overweight persons make too much leptin. Having too much leptin in the blood may contribute to insulin resistance. Paradoxically, patients who do not have any fat cells also have insulin resistance. In these patients, the resistance to the actions of insulin is caused by the absence of leptin and leptin replacement significantly improves insulin resistance and fat deposition in the liver. In an earlier study, we determined the leptin levels in patients with nonalcoholic steatohepatitis and how these levels are related to body fat levels as well as responsiveness to insulin. We saw that a subgroup of patients with NASH have relatively low levels of leptin in contrast to the amount of body fat they had. We now would like to see if restoring leptin levels to normal will improve the disease process in these patients. We will now study those patients in whom we have seen low levels of leptin. Our study patients will be male patients, aged between 18 and 65 (inclusive), who do not have any other cause for their liver disease. We have put some restrictions in body size such that a spectrum of patients from normal weight to obese range would be included. They will also demonstrate low leptin levels (levels similar to only 25 % of normal population). We will use genetically engineered form of leptin manufactured by Amgen Inc. Leptin will be given via injections under the skin. We plan to continue therapy for a period of one year and evaluate the change in liver disease by a liver biopsy. We will also follow the metabolic parameters (e.g. blood cholesterol, liver function, insulin resistance) and body composition characteristics (e.g. the pattern of fat distribution in the body) that we studied in our earlier study which we called Phase 1. We expect that patients with low blood leptin levels will show improvement in their liver disease and insulin resistance when their blood leptin levels are restored to normal. '