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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Respiration
  • Fatty Liver / complications
  • Fatty Liver / metabolism
  • Fatty Liver / pathology*
  • Female
  • Humans
  • Hydrogen Peroxide / metabolism
  • Insulin Resistance
  • Lipid Peroxidation
  • Liver / metabolism
  • Liver / pathology*
  • Male
  • Middle Aged
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology*
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Obesity / complications
  • Obesity / metabolism
  • Oxidative Stress


  • Hydrogen Peroxide