Fig. 9.

The working model of ALDH2 in regulating HMGCR stability and cholesterol synthesis. When cholesterol is accumulated, mitochondrial ALDH2 translocates to ER (presumably through MAM formation) to promote the interaction of Insig1/gp78 with HMGCR, which leads to the ubiquitination and degradation of HMGCR. However, in ALDH2 KO or ALDH2*2 liver, HMGCR is stabilized due to the attenuated interaction of Insig1 and HMGCR, resulting in increased cholesterol de novo synthesis. When cholesterol is depleted, ALDH2 predominantly resides in mitochondrial due to the decreased MAM formation, which decreases the interaction of HMGCR and Insig1, ultimately leading to stabilized HMGCR to initiate cholesterol synthesis.