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Updated: Mar 7, 2026
An Advanced Murine Model for Nonalcoholic Steatohepatitis in Association with Type 2 Diabetes
Published on: April 26, 2019
Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance
Hongzhi Chen1,2, Juli Bai1,3, Feng Dong4
1Department of Metabolism and Endocrinology, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, National Clinical Research Center for Metabolic Disease, Second Xiangya Hospital, Central South University, Changsha, China.
Abstract:
Hepatic insulin resistance and hepatosteatosis in diet-induced obesity are associated with various metabolic diseases, yet the underlying mechanisms remain to be fully elucidated. Here we show that the expression levels of the disulfide-bond A oxidoreductase-like protein (DsbA-L) are significantly reduced in the liver of obese mice and humans. Liver-specific knockout or adenovirus-mediated overexpression of DsbA-L exacerbates or alleviates, respectively, high-fat diet-induced mitochondrial dysfunction, hepatosteatosis, and insulin resistance in mice. Mechanistically, we found that DsbA-L is localized in mitochondria and that its deficiency is associated with impairment of maximum respiratory capacity, elevated cellular oxidative stress, and increased JNK activity. Our results identify DsbA-L as a critical regulator of mitochondrial function, and its down-regulation in the liver may contribute to obesity-induced hepatosteatosis and whole body insulin resistance.-Chen, H., Bai, J., Dong, F., Fang, H., Zhang, Y., Meng, W., Liu, B., Luo, Y., Liu, M., Bai, Y., Abdul-Ghani, M. A., Li, R., Wu, J., Zeng, R., Zhou, Z., Dong, L. Q., Liu, F. Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance.
Insights
Disulfide-bond A oxidoreductase-like protein (DsbA-L) deficiency in the liver worsens obesity-related metabolic issues. Restoring DsbA-L levels improves mitochondrial function and insulin resistance in mice.
Area of Science:
- Metabolic diseases
- Mitochondrial function
- Obesity research
Background:
- Hepatic insulin resistance and hepatosteatosis are linked to obesity but underlying mechanisms are unclear.
- Reduced expression of disulfide-bond A oxidoreductase-like protein (DsbA-L) is observed in the liver of obese individuals.
- DsbA-L's role in metabolic regulation requires further investigation.
Purpose of the Study:
- To investigate the role of DsbA-L in diet-induced obesity, hepatosteatosis, and insulin resistance.
- To elucidate the mechanisms by which DsbA-L influences mitochondrial function and metabolic health.
- To determine if DsbA-L can be a therapeutic target for obesity-related metabolic disorders.
Main Methods:
- Utilized liver-specific knockout and adenovirus-mediated overexpression of DsbA-L in mice fed a high-fat diet.
- Assessed mitochondrial function, including maximum respiratory capacity and oxidative stress markers.
- Measured JNK activity and evaluated levels of hepatosteatosis and insulin resistance.
Main Results:
- DsbA-L expression is significantly reduced in the livers of obese mice and humans.
- Liver-specific DsbA-L knockout exacerbated high-fat diet-induced mitochondrial dysfunction, hepatosteatosis, and insulin resistance.
- DsbA-L overexpression alleviated these diet-induced metabolic impairments.
- DsbA-L deficiency impaired mitochondrial respiration, increased oxidative stress, and elevated JNK activity.
Conclusions:
- DsbA-L is a critical regulator of hepatic mitochondrial function.
- Down-regulation of DsbA-L in the liver contributes to obesity-induced hepatosteatosis and insulin resistance.
- DsbA-L represents a potential therapeutic target for managing metabolic dysfunction in obesity.
