Diet Impact on Hepatic Transcriptomics and Lipidomics in Pre-diabetes

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, affecting 25% to 30% of the global population and nearly one third of the population in North America. NAFLD is defined as an excessive accumulation of lipids within hepatocytes in the absence of significant alcohol consumption or other causes of chronic liver disease. These patients usually present with hepatic steatosis observed on imaging studies and elevated liver enzymes with clinical features of insulin resistance (IR), including pre-diabetes, type 2 diabetes mellitus (T2DM), arterial hypertension, dyslipidemia, and visceral obesity. The minimum criterion for a histologic diagnosis of NAFLD is \>5 percent steatotic hepatocytes in a liver tissue section. The exact mechanism for the development of NAFLD is unclear, although the current evidence indicates that it is likely a complex interplay among neurohormones, intestinal dysbiosis, nutrition, and genetics. IR plays a crucial role in NAFLD pathophysiology mainly by increasing adipocyte lipolysis, resulting in the circulation of more free fatty acids available for hepatic uptake and increasing hepatic de novo lipogenesis. There is yet no approved pharmacologic option for the treatment of NAFLD. Current international guidelines on NAFLD emphasize the importance of lifestyle modifications for all patients with NAFLD and recommend 7-10% of weight loss and a "healthy diet", without suggesting any particular diet. Recent data provide some support for the beneficial role of low carbohydrate (CHO)/high unsaturated fatty acid (both monounsaturated (MUFAs) and polyunsaturated (PUFAs)) dietary patterns for decreasing hepatic steatosis. This proposal addresses this important research gap by leading to advances regarding the impact of a short-term low CHO/high PUFAs/MUFAs dietary intervention on improving hepatic gene expression profiles and lipid composition in individuals with pre-diabetes. The proposed study is unique because all meals an