Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steato hepatitis

OBJECTIVE Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites inanimals, but their role inhumans remainsunclear. This study examined the relationship of sphingolipids withhepatic and peripheralmetabolismin 21 insulinresistant obese patientswithout (NAFL2) orwith (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps with D-[6,6-2H2]glucose were performed to quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assessmitochondrial function, oxidative stress, and inflammatory activity. RESULTS Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL2, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively withwhole-body but not with hepatic insulin sensitivity. Hepaticmaximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS Sphingolipid species are not only increased in insulin-resistanthumanswithNASHbut also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans.