title: Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.
abstract: The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%-40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H2O2, lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH.
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany.
authors.forename: Chrysi
authors.initials: C
authors.lastname: Koliaki
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Szendroedi
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany.
authors.forename: Kirti
authors.initials: K
authors.lastname: Kaul
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Jelenik
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nowotny
authors.affiliation: Institute of Pathology, Heinrich Heine University, 40225, Düsseldorf, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Jankowiak
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Carstensen
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Heinrich Heine University, 40225, Düsseldorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Krausch
authors.affiliation: Department of General, Visceral and Pediatric Surgery, Heinrich Heine University, 40225, Düsseldorf, Germany.
authors.forename: Wolfram Trudo
authors.initials: WT
authors.lastname: Knoefel
authors.affiliation: General Surgery Department, St. Martinus Hospital, 40219, Düsseldorf, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schlensak
authors.affiliation: Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, 40225, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), 40225, Düsseldorf, Germany; Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, 40225, Düsseldorf, Germany. Electronic address: michael.roden@ddz.uni-duesseldorf.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Roden
mesh_terms: D000328:Adult; D019069:Cell Respiration; D005234:Fatty Liver / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007333:Insulin Resistance; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism / Q000473:pathology*; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D009765:Obesity / Q000150:complications / Q000378:metabolism; D018384:Oxidative Stress
chemical_list: D006861:Hydrogen Peroxide