Abstract
The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly. Although this condition is generally benign, accumulating evidence now suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); the leading cause of death in developed nations. Despite the well-established role of the liver as a central regulator of circulating low-density lipoprotein (LDL) cholesterol levels, a known driver of CVD, the mechanism(s) by which hepatic steatosis contributes to CVD remains elusive. Interestingly, a recent study has shown that circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels correlate positively with liver steatosis grade. Given that PCSK9 degrades the LDL receptor (LDLR) and prevents the removal of LDL from the blood into the liver, in the present study we examined the effect of hepatic steatosis on LDLR expression and circulating LDL cholesterol levels. We now report that in a manner consistent with findings in patients, diet-induced steatosis increases circulating PCSK9 levels as a result of de novo expression in mice. We also report the finding that steatosis abrogates hepatic LDLR expression and increases circulating LDL levels in a PCSK9-dependent manner. These findings provide important mechanistic insights as to how hepatic steatosis modulates lipid regulatory genes, including PCSK9 and the LDLR, and also highlights a novel mechanism by which liver disease may contribute to CVD.
Highlights
The worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing rapidly
Given that (a) proprotein convertase subtilisin/kexin type 9 (PCSK9) contributes to cardiovascular disease (CVD) by degrading the LDL receptor (LDLR) and increasing plasma low-density lipoprotein (LDL) levels [21], and (b) accumulating evidence suggests that hepatic steatosis contributes to CVD [10], we examined the effect of steatosis on hepatic LDLR expression
Immunohistochemical staining revealed that high-fat diet (HFD)-fed mice had markedly reduced cell-surface LDLR expression compared with normal control diet (NCD)-fed controls (Fig. 2B)
Summary
PCSK9 is an established driver of atherosclerotic lesion development and CVD due to its ability to enhance the degradation of cell-surface LDLR, thereby reducing the ability of the liver to clear pro-atherogenic LDL cholesterol from the circulation [13,14,15] Seminal studies in this field have shown that gain-of-function mutations in PCSK9 correlate with increased risk of CVD in humans [16], and in a reciprocal manner, loss-of-function mutations have the opposite outcome [17]. Adenoviral-mediated overexpression of PCSK9 in mice, or hepatocyte-specific transgenic overexpression of PCSK9 leads to a similar phenotype as that of the well-established LdlrϪ/Ϫ mouse model used for the study of atherosclerosis [18, 19] In line with these data, human monoclonal antibodies targeted against PCSK9 were recently shown to reduce circulating LDL cholesterol levels by up to 60% in patients at high risk of CVD [20]. Our data highlight a novel mechanism by which NAFLD may contribute to CVD by increasing PCSK9 expression to attenuate liver-mediated LDL cholesterol clearance
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