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Cell Metab. 2015 May 5;21(5):739-46. doi: 10.1016/j.cmet.2015.04.004.

Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis.

Author information

1
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.
2
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.
3
Institute of Pathology, Heinrich Heine University, 40225, Düsseldorf, Germany.
4
Department of General, Visceral and Pediatric Surgery, Heinrich Heine University, 40225, Düsseldorf, Germany.
5
General Surgery Department, St. Martinus Hospital, 40219, Düsseldorf, Germany.
6
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.

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.

PMID:
25955209
DOI:
10.1016/j.cmet.2015.04.004
[Indexed for MEDLINE]
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