FTO promotes the key mechanism of hepatic lipogenesis and the pathogenesis of NAFLD

On November 10, 2022, Ying Hao's research team from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, officially published a report entitled "Aberrant elevation of FTO levels promotes liver steatosis by decreasing the m6A methylation and" in the academic journal Journal of Molecular Cell Biology increasing the stability of SREBF1 and ChREBP mRNAs"
.
The study identified a key mechanism
in the role of fat mass and obesity-associated (FTO) genes in insulin-regulated liver fat production and NAFLD.
Hepatic FTO demethylates and stabilizes the mRNA of SREBF1 and ChREBP, thereby upregulating the expression of the key lipogenic enzymes responsible for hepatic adipogenesis, leading to hepatic steatosis
.
In addition, insulin induces the expression of hepatic FTO, which mediates part of the fat production of
insulin.
Finally, inhibition of FTO can reduce hepatic lipogenesis and TG accumulation, suggesting that FTO could be a potential target for the treatment of NAFLD
.

NAFLD has become the most common chronic liver disease, with a higher incidence than T2DM and obesity
.
It is also the fastest-growing factor in liver-related mortality globally, and there are currently no FDA-approved drugs
.
The hallmark of NAFLD is hepatic TG accumulation
.
A series of studies have shown that increasing TG production (fatty acid uptake and DNL) rather than decreasing mobilization (fatty acid oxidation and VLDL output) is the main mechanism of NAFLD development, of which DNL may be an important driver of NAFLD pathogenesis
.
Many DNL enzymes, such as ACLY, ACC1, FASN, and SCD1, are coordinated by
key transcription factors (SREBP1c and ChREBP).

N6-methyladenosine (^m6A) is the most abundant epigenetic modification, distributed in at least a quarter of mammalian mRNA, regulating mRNA metabolism
in various physiological and pathological processes.
^m6Amodification is dynamically controlled
by a group of enzymes called methyltransferases (Writer) and demethylases (Eraser).
The^m6Amodification can be recognized
by methyl reading protein (Reader).
FTO is a obesity susceptibility gene identified through genome-wide association studies (GWAS), and studies have found increased levels of FTO expression in fatty liver in rodents and NAFLD patients
.
Although FTO is known to be involved in regulating hepatic lipogenesis, the physiopathological role of FTO in hepatic lipogenesis is not fully understood
.

The study found that total RNA^m6Amethylation was reduced in mice with nonalcoholic fatty liver disease, accompanied by an increase
in FTO expression.
Hepatic overexpression of FTO promotes steteaosis
both in vivo and in vitro.
In hepatocytes, FTO overexpression specifically upregulates genes responsible for adipogenesis without affecting genes involved in fatty acid uptake/oxidation or lipoprotein output
.
Mechanistically, FTO can stabilize the mRNA of SREBF1 and ChREBP by^m6Ademethylation, resulting in increased levels of their
proteins.
Insulin therapy increases FTO expression
both in vivo and in vitro.
Inhibition of demethylase activity of FTO can reduce the expression of SREBF1, ChREBP and adipoietic genes, thereby improving the accumulation
of TG in mouse fatty liver.
The study identified the "insulin/FTO/SREBP1c/ChREBP/adipoiesis" signaling pathway, reinforcing the conclusion that
FTO is an important contributor to NAFLD.
FTO adds a dynamic gene expression regulatory mechanism
to liver fat metabolism through demethylase activity.
Targeting hepatic FTO as a strategy for the treatment of NAFLD deserves further exploration
in the future.

Zhili Tang, a doctoral student at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper, while Ying Hao, doctoral student Li Zhuoyang, and Dr.
Jiang Jingjing, Zhongshan Hospital, Affiliated Hospital of Fudan University, are the corresponding authors
of this paper.
The research was supported by the Ministry of Science and Technology and the NSFC project, as well as the public technology platform and animal platform of the Shanghai Institute of Nutrition and Health
, Chinese Academy of Sciences.

Illustration of the FTO signal path

Note: After insulin stimulation of hepatocytes, the expression of FTO increases.

FTO can stabilize the mRNA of SREBF1 and ChREBP by ^m6A demethylation, This leads to an increase in its protein levels, which ultimately promotes liver fat production, leading to hepatic steatomosis
.

Original link: https://doi.
org/10.
1093/jmcb/mjac061