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High cholesterol absorption: A risk factor of atherosclerotic cardiovascular diseases?

Piia Simonen1, Katariina Öörni2, Juha Sinisalo1

  • 1Heart and Lung Center, Cardiology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Atherosclerosis
|June 8, 2023
PubMed

Insights

High cholesterol absorption, a condition affecting one-third of the population, significantly increases atherosclerotic cardiovascular disease (ASCVD) risk. Optimizing lipid-lowering therapy with combination treatments is crucial for preventing ASCVD events.

Area of Science:

  • Cardiology
  • Metabolic Science
  • Genetics

Background:

  • Elevated low-density lipoprotein cholesterol (LDL-C) is a known risk factor for atherosclerotic cardiovascular diseases (ASCVDs).
  • Emerging evidence highlights the role of cholesterol metabolism, particularly cholesterol absorption, in ASCVD risk.
  • Understanding diverse cholesterol metabolism profiles is key to refining prevention strategies.

Purpose of the Study:

  • To investigate whether distinct cholesterol metabolism profiles, especially high cholesterol absorption, contribute to atherogenesis.
  • To explore the underlying mechanisms linking cholesterol metabolism to ASCVD risk.
  • To evaluate the impact of genetic, metabolic, and clinical factors on this association.

Main Methods:

  • Review of genetic studies on sterol transporter gene variations (ABCG5, ABCG8, NPC1L1).
  • Analysis of metabolic data related to cholesterol synthesis and elimination.
  • Examination of population-based studies and outcomes of lipid-lowering interventions.

Main Results:

  • Loss-of-function variations in ABCG5/ABCG8 lead to high cholesterol absorption, low synthesis, low elimination, and increased ASCVD risk.
  • Loss-of-function variations in NPC1L1 result in low cholesterol absorption, high synthesis, elevated elimination, and reduced ASCVD risk.
  • Statin monotherapy is insufficient for individuals with high cholesterol absorption; combination therapy (statin + cholesterol absorption inhibitor) is recommended.

Conclusions:

  • High cholesterol absorption (>60%), present in about a third of individuals, is atherogenic and elevates ASCVD risk.
  • Genetic variations in sterol transporters significantly influence cholesterol absorption and ASCVD risk.
  • Personalized lipid-lowering strategies incorporating cholesterol absorption inhibition are essential for effective ASCVD prevention.

Keywords:
ABCG5/ABCG8ASCVDCholesterol absorptionCholesterol synthesisFecal neutral sterolsLDLNPC1L1

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