Specific Hepatic Sphingolipids Relate to Insulin Resistance, Oxidative Stress, and Inflammation in Nonalcoholic Steatohepatitis

• DOI: 10.2337/dc17-1318
• Publication Date: 2018-03-30T13:15:13Z
• Authors: Maria Apostolopoulou; Ruth Gordillo; Chrysi Koliaki; Sofia Gancheva; Tomas Jelenik; Elisabetta De Fil...; Christian Herder; Daniel Markgraf; Frank Jankowiak; Irene Esposito; Matthias Schlensak; Philipp E. Scherer; Michael Roden
• Keywords: Lactosylceramide; Sphingolipid; Steatosis; Steatohepatitis

OBJECTIVE Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites in animals, but their role humans remains unclear. This study examined the relationship of sphingolipids with hepatic peripheral metabolism 21 insulin-resistant obese patients without (NAFL−) or (NAFL+) steatohepatitis (NASH) 7 healthy lean individuals undergoing tissue biopsies during bariatric elective abdominal surgery. RESEARCH DESIGN AND METHODS Hyperinsulinemic-euglycemic clamps d-[6,6-2H2]glucose were performed quantify tissue-specific insulin sensitivity. Hepatic oxidative capacity, peroxidation, phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio measured assess mitochondrial function, stress, inflammatory activity. RESULTS total ceramides higher by 50% 33% NASH compared NAFL+ NAFL−, respectively. Only dihydroceramides (16:0, 22:0, 24:1) lactosylceramides increased. Serum (hepatic 22:0 correlated negatively whole-body not maximal respiration related positively serum lactosylceramide subspecies, sphinganine, 14:0. Liver peroxides (total ceramides, sphingomyelin 22:0) pJNK-to-tJNK (ceramide 24:0; hexosylceramides 24:0, all respective sphingolipids. CONCLUSIONS Sphingolipid species are only increased also correlate stress inflammation, suggesting that these lipids may play a progression simple steatosis humans.