COMMENT:
Abnormal mitochondrial function, e.g. impaired fatty acid oxidation and oxidative phosphorylation, is an epidemiological characteristic of common metabolic disorders. Despite the protection against triglyceride accumulation they confer during early stages of metabolic disease, hepatic mitochondria may represent major drivers of oxidative stress. As such, when functionally altered, they exacerbate the development of type 2 diabetes (T2D), obesity and, thus, human steatohepatitis.
This review aims to investigate the role of hepatic mitochondrial function across the spectrum of aetiologically disparate fatty liver diseases.
KEY LEARNINGS:
During common metabolic diseases, e.g. moderately insulin-resistant obese phenotypes and early stages of obesity, hepatic mitochondrial oxidative capacity adapts to greater lipid availability, thereby preventing excessive hepatic fat accumulation. With higher-grade obesity and T2D, however, mitochondrial capacity declines. The oxidative stress which ensues favours the pathological progression of NAFLD from steatosis to steatohepatitis and, eventually, to fibrosis and cirrhosis. Mitochondrial abnormalities occurring early in NAFL include lower hepatic respiratory control ratio as well as reduced expression of genes implicated in mitochondrial biogenesis or activities of rate-controlling enzymes. Importantly, interventions directly (e.g. thyroid hormone receptor agonists) or indirectly (e.g. weight loss) impacting hepatic mitochondria demonstrate significant benefits on fatty liver diseases. This supports further therapeutic research into mitochondrial targets for fatty liver diseases. In the same vein, identifying biomarkers of abnormal function to non-invasively examine mitochondria quality may be an important NAFLD-oriented research focus.
