Molecular Cell: A novel mechanism by which cytosolic histone deacetylase SIRT6 promotes fatty acid oxidation

One of the most common chronic liver diseases is nonalcoholic fatty liver disease (NAFLD), which includes simple fatty liver disease and nonalcoholic steatohepatitis (NASH), a more serious metabolic liver disease that can increase the incidence of hepatocellular carcinoma
。 At present, the pathophysiological mechanism of NAFLD has not been fully elucidated, and there is still a lack of effective clinical treatment
.
Therefore, in-depth study of the pathogenesis of NAFLD has become a research hotspot
in the liver field and metabolism.

January 7, 2022, Zhu Weiguo/Yang Yang team is in An online publication in the journal Molecular Cell titled "Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic.
" fatty acid oxidation", revealing that in hepatocytes, palmitic acid stimulates the transport of histone deacetylase SIRT6 from the nucleus to the cytoplasm, within the cytoplasm SIRT6 increases its activity by deacetylating long-chain fatty acid CoA synthase 5 (ACSL5), promoting fatty acid oxidation, thereby improving cellular lipid utilization and ultimately resistance NAFLD process
.

Studies have found that palmitic acid-induced accumulation of SIRT6 in the cytoplasm can catalyze ACSL5 98 Deacetylation
of lysine at positions 361 and 367.
Deacetylated ACSL5 has a stronger activity of activating fatty acids, so that long-chain fatty acids enter the mitochondria more for β oxidation, thereby producing more acetyl-CoA, providing raw materials for the tricarboxylic acid cycle and improving the metabolic efficiency of fatty acids by hepatocytes
。 A high-fat-induced mouse NAFLD model found that adeno-associated virus-mediated intrahepatic ACSL5 knockdown significantly aggravated weight gain and various items in mice NAFLD indicator, while overexpression of ACSL5 can effectively inhibit NAFLD progression
in mice.
What's more, only wild-type (WT) or simulated non-acetylated (3KR) ACSL5 can hinder NAFLD Course of
disease.
A model was further constructed from high-fat-induced SIRT6 liver-specific knockout mice, which overexpressed WT, 3KR and 3KQ in the liver ACSL5
。 The study found that the ACSL5 of WT no longer exerts the function of anti-fatty liver, and only ACSL5 of 3KR can still be reversed NAFLD process
.
These results suggest that ACSL5 function depends on its deacetylation by SIRT6, SIRT6-mediated ACSL5 Deacetylation is necessary for
its anti-fatty liver function.
At the same time, the results of applying clinical NAFLD patient cohorts to validate the above mechanisms were found in NASH In the liver, cytoplasmic SIRT6 levels decreased and ACSL5 acetylation levels increased, suggesting that SIRT6 targeting was a potential intervention target for the treatment of NAFLD
。

In summary, the results of this study confirm the important function of SIRT6 in the cytoplasm in the process of fatty acid oxidation, and reveal the regulatory role of SIRT6-ACSL5 signaling axis on lipid metabolism.
It provides further verification
of the principle for targeting histone deacetylase SIRT6 to inhibit NAFLD and related metabolic diseases.

Dr.
Hou Tianyun, jointly trained by Peking University School of Basic Medicine and Shenzhen University, Cao Ziyang, Ph.
D.
of Peking University School of Basic Medicine, and Tian Yuan, Ph.
D.
of Shenzhen University Health Science Center, are the co-first authors of the paper, Shenzhen University School of Medicine Professor Zhu Weiguo, Associate Professor Yang Yang of Peking University School of Basic Medicine and Dr.
Tian Yuan of Shenzhen University School of Medicine are the corresponding authors
of the paper.
The research was strongly supported
by the National Key Research and Development Program of China, the Key Project of the National Natural Science Foundation of China, and the General Project of the National Natural Science Foundation of China.

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(School of Basic Medicine, Peking University)