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

Nat Metab. 2021 Jan;3(1):59-74. doi: 10.1038/s42255-020-00331-1. Epub 2021 Jan 18.

Authors

Yanyong Xu^#¹, Yuanyuan Li^#^{1

2

3}, Kavita Jadhav^#¹, Xiaoli Pan^{1

4}, Yingdong Zhu¹, Shuwei Hu¹, Shaoru Chen¹, Liuying Chen⁴, Yong Tang⁵, Helen H Wang⁶, Ling Yang⁴, David Q-H Wang⁶, Liya Yin¹, Yanqiao Zhang⁷

Affiliations

¹ Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA.
² Zhongshan Institute for Drug Discovery, the Institutes of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, China.
³ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
⁴ Divison of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ Department of Medicine and Genetics, Marion Bessin Liver Research Center and Albert Einstein College of Medicine, Bronx, NY, USA.
⁷ Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA. yzhang@neomed.edu.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Activating Transcription Factor 3 / physiology*
Animals
Apolipoproteins E / genetics
Atherosclerosis / prevention & control*
Bile Acids and Salts / metabolism*
Cholesterol, Dietary / metabolism
Dietary Fats / metabolism
Gene Expression Regulation / drug effects
Hepatocyte Nuclear Factor 4 / metabolism
Hepatocytes / metabolism*
Humans
Hydrocortisone / pharmacology
Lipoproteins, HDL / metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptors, LDL / genetics
Scavenger Receptors, Class B / metabolism
Steroid 12-alpha-Hydroxylase / metabolism
Tumor Suppressor Protein p53 / metabolism

Substances

ATF3 protein, human
Activating Transcription Factor 3
Apoe protein, mouse
Apolipoproteins E
Bile Acids and Salts
Cholesterol, Dietary
Dietary Fats
Hepatocyte Nuclear Factor 4
Lipoproteins, HDL
Receptors, LDL
Scarb1 protein, mouse
Scavenger Receptors, Class B
Tumor Suppressor Protein p53
Steroid 12-alpha-Hydroxylase
Hydrocortisone

Abstract

Publication types

MeSH terms

Substances

Grants and funding