Obesity and Nonalcoholic Fatty Liver Disease

The primary goal of this study is to provide a better understanding of: 1) the pathogenesis and pathophysiology of non-alcoholic fatty liver disease (NAFLD) in obese subjects, and 2) the effect of marked weight loss on the histologic and metabolic abnormalities associated with NAFLD. The following hypotheses will be tested: obesity causes hepatic fat accumulation because of excessive fatty acid release from fat tissue and increased free fatty acid availability, increased hepatic (liver) fat content causes insulin-resistant glucose (sugar) production by the liver and altered liver protein synthesis, increased hepatic fat content causes increased lipid (fat) peroxidation, hepatic inflammation, necrosis and fibrosis, and marked weight loss improves NAFLD once patients are weight stable.

Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD), which represents a spectrum of liver diseases. NAFLD is a major health problem in the US because of its high prevalence and causal relationship with serious liver abnormalities. However, the mechanism(s)responsible for developing NAFLD in obese persons and the effects on liver function are not known. This gap in knowledge has made it difficult to identify effective therapy. The results from these studies will lay the groundwork for the development of novel therapeutic interventions for NAFLD in obese patients.

Subjects, having previously diagnosed with NAFLD, were given Niacin for 16 weeks. The dosage was 500mg/day for week 1, 1000mg/day for week 2, 1500mg/day for week three and 2000mg/day for weeks 4 through 16.

Subjects were found to have intrahepatic triglyceride levels below the threshold for Non-Alcoholic Fatty Liver Disease (NAFLD). For this study that threshold was set at 10% intrahepatic triglyceride content as determined by magnetic resonance spectroscopy. These control subjects did not participate in any intervention. Only baseline features were characterized for this arm.

Subjects diagnosed with NAFLD were randomized to fenofibrate, an oral medication, nightly for eight weeks. Subjects will be given a dose of 200mg/day.

These subjects were diagnosed with Non-Alcoholic Fatty Liver Disease (NAFLD) and received an 8 week course of a placebo pill. Their baseline characteristics were averaged into the overall NAFLD baseline characteristics along with the baseline data for the two intervention groups.

Subjects randomized to Niacin therapy will be treated with Niacin at night for 16 wks to reduce plasma free fatty acid concentrations. The dose of medication will be gradually increased: 500 mg/day during week 1, 1000 mg/day during week 2, 1500 mg/day during week 3, and 2000mg/day during weeks 4-16.

Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index(HISI) is the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.

A precise measure of the ability of insulin to stimulate glucose uptake by skeletal muscle. Skeletal muscle insulin sensitivity, measured as the increase from baseline in skeletal muscle glucose uptake during insulin infusion(percentage)as part of a nine hour euglycemic hyperinsulinemic clamp study.

The ability of insulin to suppress the release of fatty acids from adipose tissue: Adipose tissue insulin sensitivity, measured as the suppression from baseline of free fatty acid release from adipose tissue (lipolysis) during insulin infusion as part of a nine hour euglycemic hyperinsulinemic clamp study.

Hepatic fat content as measured by magnetic resonance spectroscopy. A PRESS sequence was used. The results from three 10 cubic centimeter voxels positioned within the liver were averaged. The measure is a ratio of triglyceride signal to total signal.

The baseline and post-treatment measures of adipose tissue insulin sensitivity (ATIS) were compared. ATIS at both timepoints is the suppression from fasting levels of free fatty acid release from adipose tissue (lipolysis) during an insulin infusion as part of a euglycemic clamp study. It is the percent decrease from time zero to the end of the nine hour euglycemic hyperinsulinemic clamp

Changes in skeletal muscle insulin sensitivity (SMIS). SMIS was measured as the increase in skeletal muscle glucose uptake from time zero to the end of a nine hour euglycemic clamp and insulin infusion study. This increase is the percentage change from time zero to end of insulin infusion at nine hours.

Hepatic insulin sensitivity, assessed as a function of glucose production rate and plasma insulin concentration. The Hepatic Insulin Sensitivity Index (HISI) is measured as the reciprocal of glucose rate of appearance [10000/(μmol/min)] multiplied by insulin concentration[mU/L]. The 10000 in the formula is a conventional adjustment so that insulin sensitivity measures are more readable. As yet there is no normal range for HISI, since is a surrogate marker for hepatic insulin sensitivity that has not yet been validated.

Very low density lipoprotein triglyceride (VLDL-TG) production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute (μmol/L/min).

VLDL-apolipoprotein B (apoB) concentrations were measured as part of a VLDL metabolism study utilizing stable isotope tracers. VLDL apoB production rate, a measure of hepatic secretion of VLDL-apolipoproteinB-100 per liter of plasma per minute.

Very low density lipoprotein triglyceride (VLDL-Tg) clearance rate, a measure of VLDL-triglyceride removal from plasma per minute.

VLDL-TG production rate, a measure of hepatic secretion of VLDL-triglyceride per liter of plasma per minute.

Inclusion Criteria: All 18 - 45 years old Class I obesity, i.e. Body Mass Index (BMI) between 30 and 45. weight less than 300 lbs. Exclusion Criteria: Active or previous infection with hepatitis B or C, as well as other liver disease. History of alcohol abuse Diabetes Medications that cause liver damage or steatosis. Women who are pregnant or lactating.