Hyperhomocysteinemia and high-density lipoprotein metabolism in cardiovascular disease

Area of Science:

• Cardiovascular biology
• Metabolic disease research
• Atherosclerosis mechanisms

Background:

• Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease (CVD).
• The precise mechanisms by which HHcy contributes to CVD remain incompletely understood.
• Previous observations suggest an inverse correlation between homocysteine (Hcy) levels and high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoA-I) in coronary heart disease patients.

Purpose of the Study:

• To investigate the impact of HHcy on HDL-C and apoA-I metabolism.
• To elucidate the molecular mechanisms underlying Hcy-induced alterations in HDL components.
• To explore the role of Hcy in accelerating atherosclerosis.

Main Methods:

• Utilized cystathionine beta-synthase (CBS) and apolipoprotein E (apoE) double knockout mice to model HHcy and atherosclerosis.
• Measured plasma levels of HDL-C, apoA-I, and HDL particle size in HHcy mice.
• Assessed HDL function and clearance rates.
• Investigated the effects of Hcy on apoA-I synthesis and secretion in mouse primary hepatocytes and HepG2 cells, examining transcriptional regulation via PPARalpha.

Main Results:

• Severe HHcy in CBS(-/-)/apoE(-/-) mice accelerated atherosclerosis.
• HHcy led to reduced circulating HDL, apoA-I, and large HDL particles, impaired HDL function, and enhanced HDL-C clearance.
• In vitro studies showed Hcy inhibits apoA-I protein synthesis and secretion in hepatocytes.
• Hcy was also found to inhibit apoA-I transcription in HepG2 cells through PPARalpha-dependent and -independent pathways.

Conclusions:

• Hcy significantly impacts HDL metabolism by reducing HDL-C and apoA-I levels and function.
• Hcy-induced inhibition of HDL-C and apoA-I represents a novel mechanism contributing to Hcy-associated atherosclerotic cardiovascular disease.