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Introduction: Apolipoprotein O (APOO), also known as MIC26, was first discovered through a functional genomics study aimed at identifying genes differentially regulated in the heart by obesity. While its physiologic role is incompletely understood, recent studies implicate a critical intracellular role for APOO in regulating lipid metabolism. The overall objective of the present study was to determine whether genetic deletion of APOO in mice would affect cholesterol metabolism and accelerate atherosclerosis. Methods and Results: Hepatic Apoo expression was induced in response to hyperlipidemia but was inhibited after simvastatin treatment. Using a novel APOO global knockout ( Apoo -/- ) model and liver-specific APOO knockout ( Alb Cre Apoo fl/f l ) model, we report here that APOO deletion elevates hepatic and plasma cholesterol levels. Then, we bred Apoo -/- mouse onto both the Ldlr and Apoe KO hyperlipidemic mouse models. Female Apoo -/- Apoe -/- mice and Apoo -/- Ldlr -/- mice in both sexes displayed markedly elevated plasma cholesterol levels and more severe atherosclerotic lesions as compared to their littermate controls, implying the effect of APOO on cholesterol metabolism independent of LDLR and APOE. We demonstrate that APOO reduces cholesterol excretion through bile and feces. In addition, APOO deficiency led to hepatic triglycerides accumulation and decreased phospholipid unsaturation by inhibiting the expression of CYB5R3, which is responsible for hepatic fatty acid desaturation and elongation. Conclusions: These data represent the first in vivo experimental validation of the association of APOO with plasma cholesterol metabolism independent of LDLR. These results demonstrate that APOO deficiency led to the decreased CRB5R3 expression and fatty acid unsaturation, which responsible for the decrease of cholesterol excretion and elevated plasma cholesterol levels.

Objective: Metformin, a first-line drug for treating individuals with type 2 diabetes, exerts beneficial effects on cholesterol-lowering, yet its precise mechanism has not been established. Approach and Results: In 2 dyslipidemia mouse models, administration of metformin significantly decreased serum cholesterol and PCSK9 (proprotein convertase subtilisin/kexin type 9) levels, accompanied by decreased expression of PCSK9 in both mRNA and protein levels resulting in a 3-fold increase of LDLR (low-density lipoprotein receptor) in the liver. In human hepatocytes, metformin treatment suppressed the PCSK9 transcription. Depressed transcription was driven by a glucose sensor, the ChREBP (carbohydrate-responsive element-binding protein) but not by the intracellular cholesterol sensor, the SREBP2 (sterol regulatory element-binding protein 2). We further identified PCSK9 as a novel target gene of ChREBP. Metformin decreased the expression of ChREBP and inhibited its transcriptional activity by blocking its nuclear translocation attributed to the decreased intracellular glucose and glucose metabolites levels. Moreover, metformin treatment significantly decreased serum low-density lipoprotein cholesterol and PCSK9 levels in nondiabetic individuals. Conclusions: Collectively, we revealed a new mechanism of action of metformin in cholesterol-lowering and identified a novel crosstalk signal between glucose and cholesterol homeostasis via ChREBP-mediated PCSK9 regulation.