Aldehyde Dehydrogenase Mutation Exacerbated High-Fat-Diet-Induced Nonalcoholic Fatty Liver Disease with Gut Microbiota Remodeling in Male Mice

Abstract

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a critical enzyme involved in ethanol clearance in acetaldehyde metabolism and plays a key role in protecting the liver. The ALDH2*2 mutation causes a significant decrease in acetaldehyde scavenging capacity, leading to the accumulation of acetaldehyde after consuming alcohol. The prevalence of the ALDH2*2 variant is in 45% of Taiwanese individuals. ALDH2 reportedly has protective properties on myocardial damage, stroke, and diabetic retina damage. However, the effects of ALDH2 in the modulation of metabolic syndromes remain unclear. This study evaluates the roles of ALDH2 in a high-fat-diet-induced metabolic syndrome in mice. Male (M) and female (F) wild-type (WT) and ALDH2 knock-in C57BL/6J mice (4–5 weeks old) were fed a high-fat diet for 16 weeks. Results showed that the body and white-adipose-tissue weights were significantly increased in ALDH2-M compared to those in the other groups. We observed markedly elevated serum levels of alanine transaminase and glucose. Oral glucose-tolerance test and homeostasis-model assessment of insulin resistance (HOMA-IR) values were significantly higher in ALDH2-M mice than those in WT-M mice, with no observable differences in female mice. Abundant steatosis and inflammatory cells were observed in ALDH2-M, with significantly decreased expression of hepatic genes IRS2, GLUT4, and PGC-1α compared to that in WT-M. ALDH2 gene mutation also affected the β-diversity of gut microbiota in ALDH2-M resulting in the decreased abundance of Actinobacteria and an increase in Deferribacteres. Our results suggest that potential changes in gut microbiota may be associated with the defective ALDH2 exacerbation of high-fat-diet-induced liver diseases in male mice. However, female mice were not affected, and sex hormones may be an important factor that requires further investigation.

Aldehyde dehydrogenase 2 polymorphism is an important gene for insulin resistance in Japanese patients with type 2 diabetes

“…A recent study reported that ALDH2 mutant mice showed obesity-related insulin resistance, which affected the diversity of gut microbiota, decreased the abundance of Actinobacteria, and increased Deferribacteres [ 20 ]. These results suggest that ALDH2 affects obesity and insulin resistance.…”

High-Fat Diet Augments the Effect of Alcohol on Skeletal Muscle Mitochondrial Dysfunction in Mice

“…Alcohol exposure to ALDH2-knockout mice results in greater mitochondrial dysfunction [ 53 ], and ALDH2 overexpression has been shown to attenuate alcohol-induced cardiac dysfunction [ 54 ]. In addition, ALDH2 has also been shown to ameliorate HF diet-induced cardiomyopathy as well [ 55 ], and ALDH2-mutant mice with lower ALDH2 activity fed a HF diet exhibit greater metabolic syndrome and cardiac dysfunction [ 56 , 57 ]. Thus, the reduction in ALDH2 may be a factor contributing to the increased oxidative stress and diminished electron transport chain complex activity in mice exposed to HF and alcohol.…”

Association between Dietary Behaviors and BMI Stratified by Sex and the ALDH2 rs671 Polymorphism in Japanese Adults

“…It is worth mentioning that there was a female-specific negative association between the intake frequencies of soy products (natto & soy, tofu, soy milk) and BMI. Genistein, which is one of the isoflavones that is abundant in soybeans, has a reported estrogen-like effect [ 41 , 42 , 43 ]. Because estrogen decreases visceral fat accumulation via estrogen receptors [ 44 ], menopausal women have increased visceral fat [ 45 ].…”