Mitochondria and Redox Signaling in Steatohepatitis

Abstract

Alcoholic and nonalcoholic fatty liver diseases are potentially pathological conditions that can progress to steatohepatitis, fibrosis, and cirrhosis. These conditions affect millions of people throughout the world in part through poor lifestyle choices of excess alcohol consumption, overnutrition, and lack of regular physical activity. Abnormal mitochondrial and cellular redox homeostasis has been documented in steatohepatitis and results in alterations of multiple redox-sensitive signaling cascades. Ultimately, these changes in signaling lead to altered enzyme function and transcriptional activities of proteins critical to mitochondrial and cellular function. In this article, we review the current hypotheses linking mitochondrial redox state to the overall pathophysiology of alcoholic and nonalcoholic steatohepatitis and briefly discuss the current therapeutic options under investigation. Antioxid. Redox Signal. 15, 485-504.

PGC-1α overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion

“…Mitochondrial dysfunction has been proposed as a cause for the initiation and progression of hepatic steatosis through decreases in mtDNA, reduced electron transport chain oxidative capacity, and reduced hepatic FAO in human patients and rodent models (21). To our knowledge, our study is the first to examine the impact of PGC-1␣ protein overexpression on primary hepatocyte mitochondrial content and function, FAO, and TAG storage and secretion in an intact in vitro cellular system independent of circulating peripheral factors.…”

“…The mitochondrion is unique among mammalian organelles, in that it contains DNA that encodes proteins required for appropriate function (21); as such, the relative mitochondrial DNA copy number can serve as an index for mitochondrial content under differing environmental or metabolic conditions (32). In skeletal muscle, PGC-1␣ increases mtDNA content through upregulation of the nuclear-encoded mtTFA via coactivation of nuclear respiratory factors 1 and 2 (12).…”

“…The mitochondrial dysfunction associated with hepatic steatosis is observed as a variety of pathophysiologies, including deterioration of redox balance, decreased oxidative phosphorylation, damaged and/or decreased mitochondrial DNA (mtDNA), activation of mitochondrial proapoptotic events, and altered FAO (21). Previous studies examining genetic defects in mitochondrial FAO have demonstrated exaggerated development of steatosis in rodents and humans (13,29).…”

Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease

“…UCP-2-dependent mitochondrial uncoupling can be perceived as a protective mechanism to halt damage progression but compromises on the other hand the liver capacity to respond to acute high-energy demands, such as ischaemia-reperfusion injury. Additional abnormalities of hepatic energy metabolism that have been reported in human and animal NASH (rat models of high fat, methionine and choline-deficient diet) include increased ROS production, abnormal cellular and mitochondrial redox homeostasis, oxidative stress-mediated depletions of mitochondrial DNA encoding some of the polypeptide components of mitochondrial respiratory chain and increased rate of b-oxidation (Miele et al, 2003;Morris et al, 2011;Serviddio et al, 2008a;Romestaing et al, 2008) (Table 1).…”

Thymic NF-κB-inducing kinase regulates CD4+ T cell-elicited liver injury and fibrosis in mice

“…2D). Liver injury is associated with oxidative stress (20, 21); indeed, liver reactive oxygen species (ROS) levels were significantly higher in KO mice (Fig. 2E).…”