Journal
CELL METABOLISM
Volume 21, Issue 5, Pages 739-746Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.04.004
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Funding
- National Foundation of State Scholarships of Greece and European Foundation for the Study of Diabetes, EFSD
- Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW)
- German Federal Ministry of Health (BMG).
- Federal Ministry for Research (BMBF)
- Helmholtz Alliance with Universities (Imaging and Curing Environmental Metabolic Diseases, ICEMED)
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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.
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