Molecular Cell Weiguo Zhu/Yang Yang team discovered 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 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.

On October 7, 2022, the Zhu Weiguo/Yang Yang team published an online publication in Molecular Cell magazine entitled "Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation" The research paper revealed that in hepatocytes, palmitic acid stimulates the transport of histone deacetylase SIRT6 from the nucleus to the cytoplasm, and SIRT6 in the cytoplasm increases its activity by deacetylating long-chain fatty acyl-CoA synthase 5 (ACSL5), promotes fatty acid oxidation, thereby improving cellular lipid utilization and ultimately resisting the process of
NAFLD.

Palmitic acid-induced accumulation of SIRT6 in the cytoplasm was found to catalyze the deacetylation
of lysine at positions 98, 361 and 367 of ACSL5.
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.
The high-fat-induced mouse NAFLD model found that adeno-associated virus-mediated intrahepatic ACSL5 knockdown significantly aggravated the weight gain and various NAFLD indexes in mice, while overexpression of ACSL5 could effectively inhibit the NAFLD process
in mice.
What's more, only wild-type (WT) or mimic non-acetylated (3KR) ACSL5 can hinder the course
of NAFLD.
A model was further constructed from high-fat-induced SIRT6 liver-specific knockout mice to overexpress ACSL5
of WT, 3KR and 3KQ in the liver.
The study found that the ACSL5 of WT no longer exerts the function of anti-fatty liver, and only ACSL5 of 3KR can still reverse the NAFLD process
.
These results suggest that ACSL5 function depends on the deacetylation of ACSL6, and SIRT6-mediated ACSL5 deacetylation is necessary for
its anti-fatty liver function.
At the same time, the results of the clinical NAFLD patient cohort to verify the above mechanism found that the cytoplasmic SIRT6 level decreased and the ACSL5 acetylation level increased in the liver of NASH patients, 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, reveal the regulatory effect of SIRT6-ACSL5 signaling axis on lipid metabolism, and provide further verification
of the principle for targeting histone deacetylase SIRT6 to inhibit NAFLD and related metabolic diseases.

Dr.
Hou Tianyun, Ph.
D.
of 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, and Professor Zhu Weiguo of Shenzhen University School of Medicine, 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.

Original link:

style="margin-top:0;margin-bottom:0;line-height:150%;background:rgb( 255 , 255 , 255 )">

(School of Basic Medicine, Peking University)