Changes in the composition of mitochondrial electron transport chain (ETC) complexes compensate lipid overflow in early stages of hepatic steatosis

Aim Type 2 diabetes is a risk factor and a secondary disease of non-alcoholic fatty liver (NAFL). In patients with NAFL increased hepatic mitochondrial function was observed which gets lost during disease progression, however, the molecular mechanisms remain unclear. This study aims to identify the molecular mechanisms behind changes in mitochondrial activity in early stages of NAFL.

Methods Primary hepatocytes from alb-SREBP-1c mice, which feature mild hepatic steatosis with hepatic insulin resistance, were characterized for energy and glucose homeostasis. Especially mitochondrial function was analyzed both with cellular context and in isolated mitochondria by extracellular flux analysis. Moreover the specific mitochondrial proteome was analyzed by mass spectrometry.

Results In primary hepatocytes a 5-fold higher glycolysis rate without any changes in glucose or glycogen production and fatty acid uptake or oxidation was detected in alb-SREBP-1c mice. In primary hepatocytes no differences in mitochondrial substrate oxidation were observed, but overall significantly higher mitochondrial respiration in alb-SREBP-1c mice, although mitochondrial copy number was not different compared to controls. In contrast, isolated liver mitochondria showed preference for complex II-driven succinate oxidation with significant higher oxidation rates in alb-SREBP-1c. In accordance with physiological data proteome analyses showed changes in the protein composition of mitochondrial complex II.

Conclusions In hepatic steatosis model increased mitochondrial function, accompanied with significantly increased glycolysis rate counteract hepatic lipid overflow. Mitochondrial analysis points towards changed abundance of complex II subunits and subsequent increase of succinate oxidation capacity as a possible mechanism leading to increased mitochondrial function in early stages of hepatic steatosis.

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Publication History

Article published online:
06 May 2021