Hepatic DsbA‐L protects mice from diet‐induced hepatosteatosis and insulin resistance

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.

Cytosolic sensing of immuno-stimulatory DNA, the enemy within

“…have shown that aberrant activation of the cGAS–STING–IFN-I pathway exacerbates obesity-induced inflammation and insulin resistance [35]. Genetic ablation of Dsba-L, a protein chaperone localized to the mitochondrial matrix, enhanced mtDNA leakage and cGAS–STING activation in adipocytes, while over-expression protected against inflammatory responses and liver damage in obese mice [35,36]. Myocardial infarction also drives a classical IFN-I response downstream of cGAS–STING activation [37].…”

Modeling of the Weight Status and Risk of Nonalcoholic Fatty Liver Disease in Elderly Individuals: The Potential Impact of the Disulfide Bond‐Forming Oxidoreductase A‐Like Protein (DsbA‐L) Polymorphism on the Weight Status

“…Chen et al . showed that hepatic DsbA‐L protects mice from high‐fat diet‐induced fatty liver and insulin resistance.…”

“…14 In addition, it has been reported that the mRNA level of DsbA-L in adipose tissue correlated negatively with obesity in both mice and humans. 13,14 Chen et al 16 showed that the liver-specific knock-out of DsbA-L in mice exacerbated high-fat diet-induced hepatosteatosis, and the overexpression of DsbA-L protected mice against hepatosteatosis and insulin resistance. Furthermore, the suppression of DsbA-L is associated with the impairment of the respiratory capacity in mitochondria and the elevation of cellular oxidative stress.…”

“…In addition, it has been reported that the mRNA level of DsbA‐L in adipose tissue correlated negatively with obesity in both mice and humans . Chen et al . showed that the liver‐specific knock‐out of DsbA‐L in mice exacerbated high‐fat diet‐induced hepatosteatosis, and the overexpression of DsbA‐L protected mice against hepatosteatosis and insulin resistance.…”

“…showed that the liver‐specific knock‐out of DsbA‐L in mice exacerbated high‐fat diet‐induced hepatosteatosis, and the overexpression of DsbA‐L protected mice against hepatosteatosis and insulin resistance. Furthermore, the suppression of DsbA‐L is associated with the impairment of the respiratory capacity in mitochondria and the elevation of cellular oxidative stress . Recently, Bai et al .…”