Biochemical Mechanisms of Sirtuin-Directed Protein Acylation in Hepatic Pathologies of Mitochondrial Dysfunction

Abstract

Mitochondrial protein acetylation is associated with a host of diseases including cancer, Alzheimer’s, and metabolic syndrome. Deciphering the mechanisms regarding how protein acetylation contributes to disease pathologies remains difficult due to the complex diversity of pathways targeted by lysine acetylation. Specifically, protein acetylation is thought to direct feedback from metabolism, whereby nutritional status influences mitochondrial pathways including beta-oxidation, the citric acid cycle, and the electron transport chain. Acetylation provides a crucial connection between hepatic metabolism and mitochondrial function. Dysregulation of protein acetylation throughout the cell can alter mitochondrial function and is associated with numerous liver diseases, including non-alcoholic and alcoholic fatty liver disease, steatohepatitis, and hepatocellular carcinoma. This review introduces biochemical mechanisms of protein acetylation in the regulation of mitochondrial function and hepatic diseases and offers a viewpoint on the potential for targeted therapies.

The sirtuin family in health and disease

“…[434][435][436] Recent studies have suggested that SIRTs could play regulatory roles in HCC development by regulating the metabolic state of the cancer cells. 437 Referring to mitochondrial SIRTs, SIRT4 exerts a tumor-suppressive function in HCC by inhibiting glutamine metabolism. 434 SIRT5 prevents tumor immune evasion and suppresses HCC development by orchestrating bile acid metabolism.…”

Possible role of SIRT1 and SIRT3 in post-translational modifications in human breast milk during the neonatal period

“…This may even have an effect on health in later life according to the ‘concept of the first 1000 days’ (Maissan et al 2021 ). Sirtuin-directed protein acetylation/deacetylation is involved in the regulation of host of diseases and metabolic syndrome and is regarded as a potential for targeted therapies (McGinnis et al 2022 ). Protein acetylation is thought to direct feedback from metabolic mitochondrial pathways including beta-oxidation, the citric acid cycle, and the electron transport chain (McGinnis et al 2022 ).…”

The Effects of Nettle Extract Consumption on Liver PPARs, SIRT1, ACOX1 and Blood Lipid Levels in Male and Female C57Bl6 Mice

“…On an epigenetic level, the SIRT1 histone deacetylase activity was increased in bot sex. SIRT1 is a well-known key player and stress-dependent metabolic sensor that can deacetylate many downstream key transcriptional factors in both metabolism-dependent and -independent metabolic pathways to affect metabolism or mitochondrial function and biogenesis; other than PPARs, activated proteins by SIRT1 in the liver include forkhead box protein O1 (AKT/FOXOpathway), uncoupling proteins (UCP), liver X receptor (LXR), p65 protein, mTOR that activates SREBP1/2, and others [ 45 , 46 ]. SIRT1 is usually activated by the NAD/NADH ratio in cells [ 45 ].…”