CRAT links cholesterol metabolism to innate immune responses in the heart

Hua Mao, Aude Angelini, Shengyu Li, Guangyu Wang, Luge Li, Cam Patterson, Xinchun Pi, Liang Xie

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Chronic inflammation is associated with increased risk and poor prognosis of heart failure; however, the precise mechanism that provokes sustained inflammation in the failing heart remains elusive. Here we report that depletion of carnitine acetyltransferase (CRAT) promotes cholesterol catabolism through bile acid synthesis pathway in cardiomyocytes. Intracellular accumulation of bile acid or intermediate, 7α-hydroxyl-3-oxo-4-cholestenoic acid, induces mitochondrial DNA stress and triggers cGAS–STING-dependent type I interferon responses. Furthermore, type I interferon responses elicited by CRAT deficiency substantially increase AIM2 expression and AIM2-dependent inflammasome activation. Genetic deletion of cardiomyocyte CRAT in mice of both sexes results in myocardial inflammation and dilated cardiomyopathy, which can be reversed by combined depletion of caspase-1, cGAS or AIM2. Collectively, we identify a mechanism by which cardiac energy metabolism, cholesterol homeostasis and cardiomyocyte-intrinsic innate immune responses are interconnected via a CRAT-mediated bile acid synthesis pathway, which contributes to chronic myocardial inflammation and heart failure progression.

Original languageEnglish (US)
Pages (from-to)1382-1394
Number of pages13
JournalNature Metabolism
Issue number8
Early online dateJul 13 2023
StatePublished - Aug 2023


  • Animals
  • Carnitine O-Acetyltransferase/genetics
  • Cholesterol
  • Female
  • Heart Failure
  • Immunity, Innate
  • Inflammation
  • Interferon Type I
  • Male
  • Mice
  • Nucleotidyltransferases/metabolism

ASJC Scopus subject areas

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


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