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Testosterone Deficiency Promotes Hypercholesteremia and Attenuates Cholesterol Liver Uptake via AR/PCSK9/LDLR

Yu Yuefeng1, Lin Zhiqi1, Chen Yi1

  • 1Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200011, China.

International Journal of Endocrinology
|May 23, 2022
PubMed
Abstract

Insights

Testosterone deficiency impairs liver cholesterol uptake by increasing PCSK9 and decreasing LDLR via the androgen receptor pathway. This clarifies a key mechanism linking low testosterone to cholesterol metabolism.

Area of Science:

  • Endocrinology
  • Metabolic Research
  • Molecular Biology

Background:

  • Testosterone deficiency is linked to elevated plasma cholesterol, but the underlying mechanisms are not fully understood.
  • Investigating the impact of testosterone on cholesterol metabolism is crucial for understanding cardiovascular health.
  • This study aims to elucidate the molecular changes associated with testosterone deficiency and cholesterol metabolism.

Purpose of the Study:

  • To investigate the effects of testosterone deficiency on cholesterol metabolism in vivo and in vitro.
  • To identify the molecular mechanisms, including key protein changes, involved in altered cholesterol uptake.
  • To determine the role of the androgen receptor and testosterone/DHT in regulating liver cholesterol uptake.

Main Methods:

  • Utilized Sprague-Dawley rats subjected to sham-operation, subtotal orchiectomy, or orchiectomy.
  • Employed HepG2 cells cultured with varying concentrations of testosterone for in vitro analysis.
  • Applied isotope tracing and fluorescence labeling techniques to study cholesterol metabolism and analyzed key molecular regulators.

Main Results:

  • Testosterone deficiency in rats (SO and ORX groups) led to impaired liver cholesterol uptake.
  • In vitro, HepG2 cells showed reduced cholesterol uptake when exposed to low or excessive testosterone levels.
  • Lack of testosterone increased proprotein convertase subtilisin/kexin type 9 (PCSK9) and decreased low-density lipoprotein receptor (LDLR) expression.

Conclusions:

  • Testosterone deficiency attenuates liver cholesterol uptake through the PCSK9-LDLR pathway.
  • The androgen receptor (AR) acts as a mediator in this process.
  • Testosterone, rather than dihydrotestosterone (DHT), is the primary functional androgen form influencing this pathway.

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