Protein acetylation in mitochondria plays critical functions in the pathogenesis of fatty liver disease

Abstract

Background: Fatty liver is a high incidence of perinatal disease in dairy cows caused by negative energy balance, which seriously threatens the postpartum health and milk production. It has been reported that lysine acetylation plays an important role in substance and energy metabolism. Predictably, most metabolic processes in the liver, as a vital metabolic organ, are subjected to acetylation. Comparative acetylome study were used to quantify the hepatic tissues from the severe fatty liver group and normal group. Combined with bioinformatics analysis, this study provides new insights for the role of acetylation modification in fatty liver disease of dairy cows. Results: We identified 1841 differential acetylation sites on 665 proteins. Among of them, 1072 sites on 393 proteins were quantified. Functional enrichment analysis shows that higher acetylated proteins are significantly enriched in energy metabolic pathways, while lower acetylated proteins are significantly enriched in pathways related to immune response, such as drug metabolism and cancer. Among significantly acetylated proteins, many mitochondrial proteins were identified to be interacting with multiple proteins and involving in lipid metabolism. Furthermore, this study identified potential important proteins, such as HADHA, ACAT1, and EHHADH, which may be important regulatory factors through modification of acetylation in the development of fatty liver disease in dairy cows and possible therapeutic targets for NAFLD in human beings. Conclusion: This study provided a comprehensive acetylome profile of fatty liver of dairy cows, and revealed important biological pathways associated with protein acetylation occurred in mitochondria, which were involved in the regulation of the pathogenesis of fatty liver disease. Furthermore, potential important proteins, such as HADHA, ACAT1, EHHADH, were predicted to be essential regulators during the pathogenesis of fatty liver disease. The work would contribute to the understanding the pathogenesis of NAFLD, and inspire in the development of new therapeutic strategies for NAFLD.

A Comprehensive Proteome and Acetyl-Proteome Atlas Reveals Molecular Mechanisms Adapting to the Physiological Changes From Pre-laying to Peak-Laying Stage in Liver of Hens (Gallus gallus)

“…It implied that the KATs and KDACs could alter biological functions of certain proteins to adapt the physiological changes by selectively modifying different substrates and acetylated sites of the proteins. In addition, we found that (G)K, K(H), and K(Y) were the favorable Kac sites, which are confirmed by other related acetyl-proteome studies on liver (27,48,49). Further analysis of the secondary structure of the protein between acetylated and unacetylated regions revealed that, in agreement with previous findings, Kac sites were usually located in the conservatively ordered secondary structure (49), which might result in a greater chromatin opening, thus facilitating transcriptional progression (50).…”

“…Reduced acetylation of Rptor, which is a component of the mechanistic target of rapamycin kinase (Mtor) complex 1 and a key regulator of autophagy, protects mice from hepatic steatosis induced by starvation or high-fat diet (HFD) via induction of lipophagy ( 26 ). In addition, protein acetylation in mitochondria associates with important biological pathways involved in the regulation of the pathogenesis of fatty liver disease in dairy cows ( 27 ). These studies suggest that non-histone acetylation plays an important role in the regulation of liver lipid metabolism.…”

Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis

“…Indeed, it has been shown that HMGCS2 activity is regulated, negatively by acetylation [ 91 ] and positively by phosphorylation [ 92 ]. HMGCS2 is also found to be highly acetylated in fatty livers [ 93 ]. Thus, it is plausible that ectopic HMGCS2 is catalytically more active with less acetylation, whereas long-term HFD feeding acetylates endogenous mouse Hmgcs2, making it less active.…”

TMT-based quantitative proteomic analysis reveals defense mechanism of wheat against the crown rot pathogen Fusarium pseudograminearum

“…Protein extraction, trypsin digestion, LC-MS (MS/MS) analysis, and the database search were performed with reference to previously reported methods [68][69][70][71][72][73][74], with some modifications. The sample was ground into a cell powder in liquid nitrogen.…”