In humans, CE in mature HDL particles is also exchanged to LDL or VLDL particles by CETP, then the CE in these particles is absorbed by LDLR.135 In mammals, LDLR is highly expressed in the liver to mediate more than 70% of LDL-C clearance.136 LDLR deficiency is the most common cause of FH, in which patients present with markedly elevated LDL-C level and early ASCVD onset.137,138 LDLR transcription is mainly regulated by SREBP2 and can respond to changes of intracellular cholesterol.90 PCSK9 reduces LDLR expression in the post-translational manner. The gene discussed is COG2; the disease is atherosclerosis.