Mitochondrial Carriers in MAFLD
Wt HepG2
SLC25A3 KO HepG2
Copper (I) distribution of HepG2 lacking SLC25A3; Green for Cu (I) and Red for mitochondria （Exp Cell Res, 2023）
In recent years, Japan's diet has become more Westernized, and the number of people suffering from lifestyle-related diseases, mainly obesity, hyperlipidemia, and dyslipidemia, has increased every year. Nonalcoholic fatty liver disease (NAFLD) is a type of steatosis, which is not associated with alcohol intake or secondary fatty degenerations due to drugs or other diseases, and the disease can develop to nonalcoholic steatohepatitis (NASH) with progressive fibrosis, leading cirrhosis and liver cancer in some worse cases. In Japan as well as western developed countries, the prevalence of NAFLD is highly associated with overweight and obese and insulin resistance (IR) has a relevant role in pathogenesis of liver injury, resulting in NASH (1,2); therefore, NAFLD is now more often referred to as metabolic dysfunction-associated fatty liver disease (i.e., MAFLD). Substantial efforts have been made to understand the molecular etiology of NAFLD/NASH; however, it is still questioned why some patients with hepatic steatosis develop NASH but others do not.
Oxidative stress, endoplasmic reticulum stress, and autophagy are thought to be mechanisms of hepatocyte damage caused by NAFLD. Indeed, oxidative stress has been investigated as the mandatory second hit to lead NASH (3); however, recently “multiple parallel hits” model is well accepted as a rationale for the disease progression, in which the balance between pro- and anti-oxidants is lost due to accumulated lipids in the liver, such as free fatty acids (FFAs) or cholesterol (4). Experimental models indicate that mitochondrial dysfunction impairs prooxidant-antioxidant balance and decreases β-oxidation, and resultantly increased lipid accumulation facilitates generation of reactive oxygen species (ROS) production, which triggers hepatocyte death and inflammation leading tissue fibrosis. There is significant evidence for pathophysiological linkages between oxidative stress and the progression of NAFLD (5), indicating the presence of mitochondria abnormalities in NASH patients (5,6). Previous literature describes that ROS generated due to mitochondrial dysfunction induces proinflammatory cytokine production (7,8) and attenuation of the ROS scavenging system may cause hepatocellular damage.
Mitochondria are organelles that are responsible for ATP production and lipid metabolism, and material transport between the cytoplasm and mitochondria is directly linked to cell functions and many carrier proteins are expressed and mitochondrial inner membranes. Although their function is essential to maintain normal mitochondrial function, it is largely unknown how lipid accumulation affect their function. Therefore, our laboratory is focusing on mitochondrial carriers to elucidate relation between their dysfunction and progression of NAFLD/NASH.