Acetaldehyde dehydrogenase 2 interactions with LDLR and AMPK regulate foam cell formation

Area of Science:

• Biochemistry
• Cardiovascular Biology
• Genetics

Background:

• Acetaldehyde dehydrogenase 2 (ALDH2) detoxifies aldehydes and is implicated in cardiovascular disease (CVD).
• A common ALDH2 single nucleotide polymorphism (SNP), rs671, prevalent in East Asians, is linked to increased CVD incidence.
• The precise role of ALDH2 in CVD independent of alcohol consumption is not fully understood.

Purpose of the Study:

• To elucidate the non-alcoholic role of ALDH2 in atherosclerosis.
• To investigate the interaction between ALDH2 and LDLR in the context of CVD.
• To determine the molecular mechanism by which the ALDH2 rs671 SNP contributes to CVD risk.

Main Methods:

• Utilized ALDH2/LDLR and ALDH2/APOE double knockout (DKO) mouse models.
• Investigated AMPK-mediated phosphorylation and nuclear translocation of ALDH2.
• Examined the interaction of nuclear ALDH2 with HDAC3 and its effect on ATP6V0E2 transcription.
• Analyzed the impact of LDLR interaction with AMPK on ALDH2 phosphorylation.
• Studied the ALDH2 rs671 mutant in human macrophages.

Main Results:

• ALDH2/LDLR DKO mice showed reduced atherosclerosis, while ALDH2/APOE DKO mice exhibited increased atherosclerosis.
• In LDLR-deficient conditions, AMPK phosphorylates ALDH2, promoting its nuclear translocation and repression of ATP6V0E2.
• LDLR's interaction with AMPK inhibits ALDH2 phosphorylation; this interaction is attenuated by the ALDH2 rs671 mutation.
• The ALDH2 rs671 mutation leads to nuclear ALDH2, suppressed ATP6V0E2 expression, impaired lysosomal function, and increased foam cell formation.

Conclusions:

• ALDH2 and LDLR have a complex, interacting role in atherosclerosis.
• Nuclear ALDH2 represses ATP6V0E2, impacting lysosomal function and lipid metabolism.
• The ALDH2 rs671 SNP confers CVD risk by disrupting this regulatory pathway, leading to increased foam cell formation and atherosclerosis.