Activating transcription factor (ATF) 6 upregulates cystathionine β synthetase (CBS) expression and hydrogen sulfide (H2S) synthesis to ameliorate liver metabolic damage

Abstract

Activating transcription factor 6 (ATF6) is an endoplasmic reticulum stress responsive gene. We previously reported that conditional knockout of hepatic ATF6 exacerbated liver metabolic damage by repressing autophagy through mTOR pathway. However, the mechanism by which ATF6 influence liver metabolism has not been well established. Hydrogen sulfide (H₂S) is a gaseous signaling molecule that plays an important role in regulating inflammation, and suppress nonalcoholic fatty liver in mice. Based on the previous study, we assumed that ATF6 may regulate H₂S production to participate in liver metabolism. In order to clarify the mechanism by which ATF6 regulates H₂S synthesis to ameliorate liver steatosis and inflammatory environment, we conducted the present study. We used the liver specific ATF6 knockout mice and fed on high-fat-diet, and found that H₂S level was significantly downregulated in hepatic ATF6 knockout mice. Restoring H₂S by the administration of slow H₂S releasing agent GYY4137 ameliorated the hepatic steatosis and glucose tolerance. ATF6 directly binds to the promoter of cystathionine β synthetase (CBS), an important enzyme in H₂S synthesis. Thus, ATF6 could upregulate H₂S production through CBS. Sulfhydrated Sirtuin-1 (SIRT1) was downregulated in ATF6 knockout mice. The expression of pro-inflammatory factor IL-17A was upregulated and anti-inflammatory factor IL-10 was downregulated in ATF6 knockout mice. Our results suggest that ATF6 can transcriptionally enhance CBS expression as well as H₂S synthesis. ATF6 increases SIRT1 sulfhydration and ameliorates lipogenesis and inflammation in the fatty liver. Therefore, ATF6 could be a novel therapeutic strategy for high-fat diet induced fatty liver metabolic abnormalities.