Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global pandemic that affects one-quarter of the world’s population. NAFLD includes a spectrum of progressive liver disease from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis and can be complicated by hepatocellular carcinoma. It is strongly associated with metabolic syndromes, obesity, and type 2 diabetes, and it has been shown that metabolic dysregulation is central to its pathogenesis. Recently, it has been suggested that metabolic- (dysfunction) associated fatty liver disease (MAFLD) is a more appropriate term to describe the disease than NAFLD, which puts increased emphasis on the important role of metabolic dysfunction in its pathogenesis. There is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Impaired mitochondrial fatty acid oxidation and, more recently, a reduction in mitochondrial quality, have been suggested to play a major role in NAFLD development and progression. In this review, we provide an overview of our current understanding of NAFLD and highlight how mitochondrial dysfunction contributes to its pathogenesis in both animal models and human subjects. Further we discuss evidence that the modification of mitochondrial function modulates NAFLD and that targeting mitochondria is a promising new avenue for drug development to treat NAFLD/NASH.

Aging and aging-related diseases: from molecular mechanisms to interventions and treatments

“…Mitochondrial dysfunction has been linked to a reduction in fatty acid β-oxidation (FAO) that is due to decreased carnitine palmitoyl transferase-1 (CPT-1) activity and decreased fatty acid clearance, resulting in the pathogenesis of NAFL. 295 Moreover, impaired hepatic FAO is related to the progression of NAFLD in patients with obesity. During NAFLD, the impairment of FAO inhibits the activity of PPARα, resulting in hepatic lipid accumulation and inflammation.…”

“…With aging, impairment of hepatic autophagy in the fatty liver may fail to remove damaged mitochondria, therefore leading to activation of the mitochondrial death pathway and causing NASH via oxidative stress and apoptosis. 295 In general, the liver has a remarkable capacity for regeneration and restoration. However, age-mediated changes impair the hepatic regenerative capacity.…”

The Aging Human Liver: The Weal and Woe of Evolutionary Legacy

“…NAFLD has emerged as the most prevalent chronic liver disease. Consisting of steatotic nonalcoholic fatty liver (NAFL) in its earlier phase and inflammatory nonalcoholic steatohepatitis (NASH) as a late-stage exacerbation, this major pandemic currently affects close to 30 % of the global population [2,3]. In addition, NAFLD is a leading cause of HCC [4], with NASH being the foremost risk factor for developing this type of cancer [5].…”

In vivo recognition of bioactive substances of Polygonum multiflorum for regulating mitochondria against metabolic dysfunction-associated fatty liver disease

“…The study found that mitochondrial dysfunction plays a significant role in the development of MAFLD. The oxidative damage of mitochondrial fatty acids and the decline of mitochondrial quality are considered to be extremely important motivations in the development of MAFLD[ 5 ]. Thus, modulation of mitochondrial function may be an effective strategy to alleviate MAFLD.…”