Related Experiment Video

Updated: Jul 4, 2026

Cholesterol Efflux Assay
07:54

Cholesterol Efflux Assay

Published on: March 6, 2012

HDAC9 promotes atherosclerosis by suppressing CYP7A1 and impairing hepatic cholesterol excretion

Rongzhan Lin1,2, Mingjue Li2, Jichen Liu1

  • 1Department of Cardiology, Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Clinical Science (London, England : 1979)
|July 3, 2026
PubMed

Insights

Histone deacetylase 9 (HDAC9) worsens atherosclerosis by inhibiting bile acid synthesis, a key cholesterol excretion pathway. Targeting hepatic HDAC9 may offer new treatments for high cholesterol and atherosclerosis.

Area of Science:

  • Cardiovascular Biology
  • Molecular Metabolism
  • Atherosclerosis Research

Background:

  • Histone deacetylase 9 (HDAC9) is implicated in atherosclerosis via inflammatory pathways.
  • Its precise role in cholesterol metabolism, particularly hepatic cholesterol excretion, requires further investigation.

Purpose of the Study:

  • To determine if HDAC9 promotes atherosclerosis by impairing hepatic cholesterol excretion through bile acid synthesis.
  • To elucidate the molecular mechanisms linking HDAC9 to cholesterol metabolism and atherosclerosis.

Main Methods:

  • Utilized ApoE-/- and ApoE-/-PSRC1-/- mouse models fed a high-fat diet (HFD).
  • Administered pharmacological HDAC9 inhibitor (TMP195) and liver-targeted AAV8-shHdac9 for gene knockdown.
  • Conducted in vitro assays using Hep1-6 and HepG2 hepatocytes.
  • Analyzed hepatic HDAC9 expression, CYP7A1 activity, plasma LDL-C levels, and aortic plaque burden.

Main Results:

  • HFD feeding and PSRC1 deficiency upregulated hepatic HDAC9 and suppressed CYP7A1, the rate-limiting enzyme in bile acid synthesis.
  • HDAC9 inhibition or knockdown restored CYP7A1, reduced LDL-C, and decreased aortic plaque in HFD-fed ApoE-/- mice.
  • In vitro, HDAC9 knockdown reduced cholesterol accumulation, while overexpression exacerbated it.
  • HDAC9 was found to transcriptionally repress Cyp7a1, mediating its cholesterol-lowering effects.

Conclusions:

  • HDAC9 promotes atherosclerosis by transcriptionally repressing Cyp7a1, thereby impairing bile acid synthesis and hepatic cholesterol excretion.
  • These effects are independent of HDAC9's known inflammatory roles.
  • Hepatic HDAC9 represents a potential therapeutic target for hypercholesterolemia and atherosclerosis.

Keywords:
CYP7A1HDAC9 inhibitoratherosclerosischolesterol excretionhypercholesterolemia

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