Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism.

Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism.

Xu Y;Li Y;Jadhav K;Pan X;Zhu Y;Hu S;Chen S;Chen L;Tang Y;Wang HH;Yang L;Wang DQ;Yin L;Zhang Y

Nature Metabolism

2021

2021-01

Activating transcription factor (ATF)3 is known to have an anti-inflammatory function, yet the role of hepatic ATF3 in lipoprotein metabolism or atherosclerosis remains unknown. Here we show that overexpression of human ATF3 in hepatocytes reduces the development of atherosclerosis in Western-diet-fed Ldlr(-/-) or Apoe(-/-) mice, whereas hepatocyte-specific ablation of Atf3 has the opposite effect. We further show that hepatic ATF3 expression is inhibited by hydrocortisone. Mechanistically, hepatocyte ATF3 enhances high-density lipoprotein (HDL) uptake, inhibits intestinal fat and cholesterol absorption and promotes macrophage reverse cholesterol transport by inducing scavenger receptor group B type 1 (SR-BI) and repressing cholesterol 12α-hydroxylase (CYP8B1) in the liver through its interaction with p53 and hepatocyte nuclear factor 4α, respectively. Our data demonstrate that hepatocyte ATF3 is a key regulator of HDL and bile acid metabolism and atherosclerosis.

atherosclerosis

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NEOMED College of Medicine

Department of Integrative Medical Sciences

NEOMED Postdoc Publications

February 2021 List