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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)59-74
Number of pages16
JournalNature Metabolism
Volume3
Issue number1
DOIs
StatePublished - Jan 2021

ASJC Scopus subject areas

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

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