Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation

Wang, Shirong; Zha, Lin; Cui, Xin; Yeh, Yu-Ching; Liu, Ruochuan; Jia, Jing; Shi, Huidong; Chen, Weiping; Hanover, John A.; Yin, Jun; Yu, Liqing; Xue, Bingzhong; Shi, Hang

doi:10.1002/advs.202206068

Cited by 8 publications

(2 citation statements)

References 53 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Four other hepatocyte‐specific DNA methylation mutants are particularly relevant for this study—deletions of the maintenance methyltransferase Dnmt1 , 32 Dnmt1 and Dnmt3a , 60 the DNA demethylases Tet2 and Tet3 , 8 and liver‐specific Dnmt3b 61 . The phenotypic effects of these hepatocyte‐specific deletions of methyltransferases and demethylases differed from Dnmt3a/3b deletion (DKO).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Liver‐specific deletion of de novo DNA methyltransferases protects against glucose intolerance in high‐fat diet‐fed male mice

Yao,

Prates,

Freydenzon

et al. 2024

The FASEB Journal

View full text Add to dashboard Cite

Alterations to gene transcription and DNA methylation are a feature of many liver diseases including fatty liver disease and liver cancer. However, it is unclear whether the DNA methylation changes are a cause or a consequence of the transcriptional changes. It is even possible that the methylation changes are not required for the transcriptional changes. If DNA methylation is just a minor player in, or a consequence of liver transcriptional change, then future studies in this area should focus on other systems such as histone tail modifications. To interrogate the importance of de novo DNA methylation, we generated mice that are homozygous mutants for both Dnmt3a and Dnmt3b in post‐natal liver. These mice are viable and fertile with normal sized livers. Males, but not females, showed increased adipose depots, yet paradoxically, improved glucose tolerance on both control diet and high‐fat diets (HFD). Comparison of the transcriptome and methylome with RNA sequencing and whole‐genome bisulfite sequencing in adult hepatocytes revealed that widespread loss of methylation in CpG‐rich regions in the mutant did not induce loss of homeostatic transcriptional regulation. Similarly, extensive transcriptional changes induced by HFD did not require de novo DNA methylation. The improved metabolic phenotype of the Dnmt3a/3b mutant mice may be mediated through the dysregulation of a subset of glucose and fat metabolism genes which increase both glucose uptake and lipid export by the liver. However, further work is needed to confirm this.

show abstract

Section: Discussionmentioning

confidence: 99%

“…The AAV‐cre‐driven deletions of Dnmt1 and Dnmt3a reduced liver steatosis in HFD‐fed mice 60 . The authors attributed this to the deletions reducing DNA methylation at the Beta‐klotho ( Klb ) promoter, thus increasing expression and the downstream increases of lipid oxidation in the liver.…”

Section: Discussionmentioning

confidence: 99%

Liver‐specific deletion of de novo DNA methyltransferases protects against glucose intolerance in high‐fat diet‐fed male mice

Yao,

Prates,

Freydenzon

et al. 2024

The FASEB Journal

View full text Add to dashboard Cite

show abstract

Epigenetic Regulation of Hepatic Lipid Metabolism by DNA Methylation

et al. 2023

Self Cite

View full text Add to dashboard Cite

While extensive investigations have been devoted to the study of genetic pathways related to fatty liver diseases, much less is known about epigenetic mechanisms underlying these disorders. DNA methylation is an epigenetic link between environmental factors (e.g., diets) and complex diseases (e.g., non-alcoholic fatty liver disease). Here, it is aimed to study the role of DNA methylation in the regulation of hepatic lipid metabolism. A dynamic change in the DNA methylome in the liver of high-fat diet (HFD)-fed mice is discovered, including a marked increase in DNA methylation at the promoter of Beta-klotho (Klb), a co-receptor for the biological functions of fibroblast growth factor (FGF)15/19 and FGF21. DNA methyltransferases (DNMT) 1 and 3A mediate HFD-induced methylation at the Klb promoter. Notably, HFD enhances DNMT1 protein stability via a ubiquitination-mediated mechanism. Liver-specific deletion of Dnmt1 or 3a increases Klb expression and ameliorates HFD-induced hepatic steatosis. Single-nucleus RNA sequencing analysis reveals pathways involved in fatty acid oxidation in Dnmt1-deficient hepatocytes. Targeted demethylation at the Klb promoter increases Klb expression and fatty acid oxidation, resulting in decreased hepatic lipid accumulation. Up-regulation of methyltransferases by HFD may induce hypermethylation of the Klb promoter and subsequent down-regulation of Klb expression, resulting in the development of hepatic steatosis.

show abstract