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

Yanyong Xu; Yuanyuan Li; Kavita Jadhav; Xiaoli Pan; Yingdong Zhu; Shuwei Hu; Shaoru Chen; Liuying Chen; Yong Tang; Helen H. Wang; Ling Yang; David Q.H. Wang; Liya Yin; Yanqiao Zhang

doi:10.1038/s42255-020-00331-1

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

Yanyong Xu, Yuanyuan Li, Kavita Jadhav, Xiaoli Pan, Yingdong Zhu, Shuwei Hu, Shaoru Chen, Liuying Chen, Yong Tang, Helen H. Wang, Ling Yang, David Q.H. Wang, Liya Yin, Yanqiao Zhang

Medicine

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	59-74
Number of pages	16
Journal	Nature Metabolism
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s42255-020-00331-1
State	Published - Jan 2021

ASJC Scopus subject areas

Physiology (medical)
Internal Medicine
Endocrinology, Diabetes and Metabolism
Cell Biology

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title = "Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism",

abstract = "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.",

author = "Yanyong Xu and Yuanyuan Li and Kavita Jadhav and Xiaoli Pan and Yingdong Zhu and Shuwei Hu and Shaoru Chen and Liuying Chen and Yong Tang and Wang, {Helen H.} and Ling Yang and Wang, {David Q.H.} and Liya Yin and Yanqiao Zhang",

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year = "2021",

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doi = "10.1038/s42255-020-00331-1",

language = "English (US)",

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T1 - Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism

AU - Xu, Yanyong

AU - Li, Yuanyuan

AU - Jadhav, Kavita

AU - Pan, Xiaoli

AU - Zhu, Yingdong

AU - Hu, Shuwei

AU - Chen, Shaoru

AU - Chen, Liuying

AU - Tang, Yong

AU - Wang, Helen H.

AU - Yang, Ling

AU - Wang, David Q.H.

AU - Yin, Liya

AU - Zhang, Yanqiao

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

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

Abstract

ASJC Scopus subject areas

UN SDGs

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