Zhu Weiguo of Peking University and other teams have discovered potential targets for the treatment of nonalcoholic fatty liver disease

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Written by Mia

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide and has become a serious public health problem
.
In addition, NAFLD and its progressive form, nonalcoholic steatohepatitis (NASH), are rapidly becoming the leading cause
of hepatocellular carcinoma (HCC).
Although some drugs are in clinical trials, there are no effective drugs to treat or prevent NAFLD
.

On October 7, Zhu Weiguo and Yang Yang of Peking University and Tian Yuan's team from Shenzhen University jointly published a paper entitled "Cytoplasmic SIRT6-mediated ACSL5 deacetylation impedes nonalcoholic fatty liver disease by facilitating hepatic fatty acid oxidation" on Molecular Cell ".

This study suggests that cytoplasmic SIRT6-mediated ACSL5 deacetylation hinders nonalcoholic fatty liver disease
by promoting hepatic fatty acid oxidation.

https://doi.
org/10.
1016/j.
molcel.
2022.
09.
018

Overview of the study

 01 

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of lipids in the liver that can develop into nonalcoholic steatohepatitis (NASH).

Histone deacetylase SIRT6 (SIRT6) regulates NAFLD by regulating metabolism-related gene expression, but the extrachromosomal role
of SIRT6 in the development of NAFLD is unclear.

The study analyzed whether SIRT6 acted
on NAFLD in the cytoplasm.
The researchers found that SIRT6 binds to saturated fatty acids, specifically palmitic acid
.
This binding leads to its nuclear output, where it deacetylates long-chain acyl-CoA synthase 5 (ACSL5), thereby promoting fatty acid oxidation
.
High-fat diet-induced NAFLD can be inhibited by ACSL5 hepatic overexpression, but its depletion is exacerbated
.

As a validation, the researchers found that overexpression of deacetylated ACSL5 mimicked weakened NAFLD
in Sirt6 liver-specific knockout mice.
In addition, cytoplasmic SIRT6 levels were significantly reduced and ACSL5 acetylation increased
in NASH-liver tissue of both patients and diet-fed mice.
Therefore, the SIRT6/ACSL5 signaling pathway plays a key role in the progression of NAFLD and is expected to be a pathway
for therapeutic intervention.

Recent non-alcoholic fatty liver disease research

 02 

On July 7, 2022, the team of Kong Lingyi and Zhang Hao of China Pharmaceutical University jointly published a paper entitled "RNA helicase DEAD-box protein 5 alleviates nonalcoholic steatohepatitis progression via tethering TSC complex and suppressing mTORC1" at Hepatology signaling"
.
The study found that DDX5 expression was downregulated
in the liver of NASH patients and mouse models, as well as in palmitic acid (PA)-stimulated hepatocytes.

Adeno-associated virus-mediated overexpression of DDX5 improves hepatic steatosis and inflammation, while its absence aggravates this pathology
.
Through non-targeted metabolomics analysis, the researchers explored the mechanism of DDX5 in NASH and NASH-hcc, suggesting the regulatory effect
of DDX5 on lipid metabolism.
DDX5 inhibits mTORC1 activation by recruiting TSC1/2 complex to mTORC1, thereby improving lipid metabolism and attenuating NLRP3 inflammasome activation
.
The study further found that the phytochemical compound HK interacts directly with DDX5 and prevents its ubiquitination degradation mediated by the E3 ligase TRIM5, thereby significantly reducing lipid accumulation and inflammation
in a mouse model of NASH.

On July 15, 2022, the team of Sun Ying of Xuzhou Medical University published a research paper
entitled "Inhibition of mPGES-2 ameliorates NASH by activating NR1D1 via heme" in Hepatology.
The study found that mPGES-2-deficient mice had reduced liver lipid accumulation and improved
liver damage, inflammation and fibrosis compared with control mice.

In addition, mPGES-2 lacks a protective effect against NAFLD dependent on lowering cytochrome P450 4A14 and increasing acyl-CoA thioesterase 4 levels (regulated by heme receptor nuclear receptor subfamily 1 group D member 1).

Heme regulates elevated NR1D1 activity mediated by mPGES-2 deficiency
.
The study also further confirmed the protective effect
of the mPGES-2 inhibitor SZ0232 in the treatment of NAFLD.

On August 5, 2022, the team of Li Pingping of the Chinese Academy of Medical Sciences and the team of Huang Zhifeng of Wenzhou Medical University jointly published a study
entitled "Hepatocyte leukotriene B4 receptor 1 promotes NAFLD development in obesity" at Hepatology.
The study found that hepatocyte-specific knockout (HKO) of Ltb4R1 improved diet-induced and gene-induced hepatic steatosis and systemic insulin resistance
in obese mice.
In Ltb4r1 SKO obese mice, levels of mRNA, the key enzymes involved in de novo adipogenesis (DNL) and fatty acidification
, decreased.
LTB4/Ltb4r1 directly promotes adipogenesis
in HepG2 cells and primary hepatocytes.

Mechanistically, LTB4/Ltb4r1 promotes adipogenesis by activating the cAMP-PKA-IRE1α-XBP1s axis in hepatocytes, thereby promoting the expression
of adipoietic genes regulated by XBP1s.
In addition, inhibition of Ltb4r1 by Ltb4r1 inhibitor or lentivirus-short hairpin RNA delivery can alleviate fatty liver phenotyping
in obese mice.

Resources:

style="margin: 0px 0px 15px;white-space: normal;padding: 0px;box-sizing: border-box;">https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32708

https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32671

https://aasldpubs.
onlinelibrary.
wiley.
com/doi/10.
1002/hep.
32651

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.