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

C Koliaki, J Szendroedi, K Kaul, T Jelenik, P Nowotny… - Cell metabolism, 2015 - cell.com
C Koliaki, J Szendroedi, K Kaul, T Jelenik, P Nowotny, F Jankowiak, C Herder…
Cell metabolism, 2015cell.com
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 …
Summary
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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