Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease affecting about 30% of the U.S. population. The prognosis for simple liver steatosis is relatively benign; however, chronic inflammation and progressive fibrosis may lead to nonalcoholic steatohepatitis (NASH) and later to cirrhosis and hepatocellular carcinoma. There is no established treatment to stop progression from NAFLD to NASH to date. Therefore, we developed a protocol to investigate the acute impact of saturated (SFA) and monounsaturated (MUFA) fatty acids on liver energy metabolism and their potential lipotoxic effects. Conscious, unrestrained, overnight fasted 12 weeks old male C57Bl/6J mice were given continuous, intravenous infusions of either saline, 20% lard oil or 20% olive oil emulsions (as described in Stein DT et al. J Clin Invest. 1997; 100 (2): 398-403) for 5 hrs. Lipid infusion was accompanied by primed, continuous infusion of [6,6-2H2] glucose (16mg/kg/min for 5 min and 0.8 mg/kg/min continuously) and sodium [13C3]lactate (200 μM/kg/min 5 min and 40 μM/kg/min continuously) intravenously for 4 and 2 hrs, respectively. Both plasma and liver free fatty acids were upregulated in SFA and MUFA groups. However, liver triglycerides, alanine aminotransferase (ALT) and aspartate transaminase (AST) were significantly increased, whereas plasma insulin and glucose levels significantly decreased, only in the MUFA group. 13C and 2H-enrichment of plasma glucose and liver alanine, glutamate, lactate and urea obtained at the end of the study were measured by GC-MS and used to regress liver metabolic fluxes using a flexible flux modeling platform (INCA). We observed that both SFA and MUFA increased the absolute rate of dihydroxyacetone phosphate (DHAP) flux from glycerol. Absolute flux of acetyl-CoA production was shifted from synthesis through pyruvate dehydrogenase toward increased contribution from fatty acid oxidation. On the other hand, only MUFA decreased the gluconeogenesis rate.
T. Bednarski: None. M. Rahim: None. J. Young: Consultant; Self; Pfizer Inc. Stock/Shareholder; Self; Metalytics.
National Institutes of Health (R01DK106348)