Direct Contribution of Mitochondorial Oxidative Stress to Hepatic Fibrogenesis

Background & Aims: Oxidative stress is generally considered to play a key role in the progression of chronic liver diseases. Here we examined the underlying mechanisms by using "Tet-mev-1" mice that harbor a doxycycline (Dox)-inducible mutant succinate dehydrogenase gene of the electron transport system in mitochondria.
Methods: Primary hepatocytes from wild type or Tet-mev-1 mice were treated with Dox, and ROS generation and decreased mitochondrial membrane potential were detected by DCFDA and TMRM fluorescence, respectively. Activation of type I collagen gene (Col1a2) promoter was examined by co-culture with hepatic stellate cells (HSC) from Col1a2/luciferase reporter mice. Wild type and Tet-mev-1 mice were fed high fat/high sucrose (HFHS) diet, and RNA extracted from the excised liver tissue was subjected to cDNA microarray and quantitative PCR analyses.
Results: Ros generation was increased 1.4-fold and mitochondrial membrane potential was decreased in Dox-treated Tet-mev-1 hepatocytes. Col1a2 promoter was activated 3.5-fold in HSC co-cultured with Tet-mev-1 hepatocytes compared to those with wild type hepatocytes. Expression of MCP-1, MIP-1α and MIP-1β mRNA was remarkably increased in liver tissue from Tet-mev-1 mice fed HFHS diet as compared with those with normal diet.
Conclusion: High fat diet and mitochondrial oxidative stress synergistically increase CC chemokine expression and activate Col1a2 promoter in the liver. Tet-mev-1 mice provide a unique system to evaluate direct contribution of oxidative stress to hepatic fibrogenesis.