BATF relieves hepatic steatosis by inhibiting PD1 and promoting energy metabolism

Reviewer #1 (Public Review):

The authors investigated the function of BATF in hepatic lipid metabolism. They found BATF alleviated high-fat diet (HFD)-induced hepatic steatosis. In addition, BATF could inhibit programmed cell death protein (PD)1 expression induced by HFD. By using over expression and transcriptional activity analysis, this study confirmed that BATF regulates fat accumulation by inhibiting PD1 expression and promoting energy metabolism. Then, they found PD1 antibodies alleviated hepatic lipid deposition. These data identified the regulatory role of BATF in hepatic lipid metabolism and that PD1 is a target for alleviation of NAFLD.

The conclusions of this manuscript are supported by data, but some remaining concerns need to be addressed.

1. There are different cells in liver tissue, in which BATF protein is expressed most.
2. The statistical data should be provided to support the liver specific over-expression of BATF.
3. For in vivo study, food intake is key data to exclude the change of energy intake.
4. For Fig.6 Since PD1 are also highly expressed in heart and spleen, how to exclude the effect of PD1 antibody on these tissues?

Reviewer #2 (Public Review):

In this manuscript, authors firstly investigated the role of a transcriptional factor BATF in hepatic lipid metabolism both in vivo and in vitro. By using a AAV transfection to overexpress BATF in liver, the mice with overexpression of BATF resisted the high fat diets induced obesity and attenuated the hepatic steatosis. Mechanically, the PD1 mediated its effect on lipid accumulation in hepatocyte and IL-27 mediated its effect on adiposity reduction in vivo.

Strength

1. This work found the transcription factor BATF was positive to reduce hepatic lipid accumulation and offered a potential target to treat NAFLD.
2. PD1 antibody is always used to treat cancer, authors here have developed its new function in metabolic disease. PD1 antibody could help mice to combat obesity and hepatic steatosis induced by high fat diets.
3. Overexpression of BATF in the liver not only decreased the lipid accumulation in the liver but also reduced the fat mass. IL-27 secretion in the liver was enhanced to affect the adipose tissue. The cross talk in liver and adipose tissue was also validated in this paper.

Weakness

1. BATF protein is also abundantly expressed in control hepatocyte, but the knockdown of BATF had no effect on lipid accumulation. Besides, the expression of BATF was elevated by high fat diets. So it will be interesting to investigate its role in the liver by using its hepatic conditional knockout mice.
2. The data for the direct regulation of BATF on PD1 and IL-27 is not enough, it is better to carry out CHIP experiment to further confirm it.