Serum and hepatic sphingolipids relate to insulin resistance, hepatic mitochondrial capacity and oxidative stress in non-alcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes. Ceramide species in liver and plasma are related to hepatic steatosis and hepatic insulin resistance in rodents, but their role for human insulin resistance and NAFLD remains unclear. To examine the relationship between total and specific sphingolipids with insulin sensitivity and NAFLD, we examined 14 obese patients with or without NAFLD and 7 healthy lean individuals (CON), who underwent liver biopsies during bariatric surgery or elective abdominal surgery. Before surgery, hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]glucose were performed to measure hepatic and peripheral insulin sensitivity. Hepatic oxidative capacity, H2O2 and lipid peroxidation were measured to assess mitochondrial function and oxidative stress. Total hepatic, but not serum ceramides were 8% and 19% higher in NAFLD+ compared to NAFLD- and CON. Only NAFLD+ had higher liver dihydroceramides 16:0 and 24:0, sphingosine and sphinganine. Serum ceramide species 14:0, 16:0 and 20:0, total dihydroceramides, dihydroceramide 16:0, 20:0 and 22:0 correlated negatively with peripheral insulin sensitivity (all r> 0.55, p < 0.05). Hepatic maximal respiration correlated positively to total and certain serum dihydroceramides, liver lactosylceramide 16:0 and sphingomyeline 18:0 (all r> 0.50, p < 0.05). Liver hepatic H2O2 (ceramide 16:0, certain hexosyl- and lactosylceramides) and lipid peroxide concentrations (dihydroceramide 24:1, total ceramides, ceramide 24:1) correlated positively with the respective hepatic sphingolipids (r> 0.47, p < 0.05). In conclusion, specific sphingolipids are increased in obese people with NAFLD and correlate with higher oxidative capacity and oxidative stress in liver, thereby suggesting a possible role of sphingolipids in the progression of NAFLD.