New Insights Into the Regulation of Lipoprotein Metabolism by PCSK9: Lessons From Stable Isotope Tracer Studies in Human Subjects

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation.

Low Lipoprotein(a) Levels Predict Hepatic Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

“…( 45 ) Supporting these observations, PCSK9 inhibitors reduce circulating Lp(a). ( 46 ) However, the effect of the PCSK9 rs7552841 mutation on Lp(a) did not translate to significant protection against fibrosis onset in our cohort and in the UKBBC (data not shown).…”

Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target

“…These PCSK9 inhibitors are used to treat primary hyperlipidemia and have been found to reduce myocardial infarction and stroke in persons with established CVD [ 227 , 228 ]. The PCSK9 enzyme enhances degradation of the LDL receptor; therefore, its inhibition allows for greater accumulation of this receptor, enhancing clearance of apoB-containing lipoproteins and reducing the LDL and apoB particle number [ 229 , 230 ]. It has been suggested that if the target LDL-C level is not achieved with the maximum tolerated statin dose, the next adjunctive therapy to add after ezetimibe would be a PCSK9 inhibitor [ 231 , 232 ].…”

PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology

“…Statins increase the activity of LDLRs, thus increasing the catabolism of VLDL, LDL and intermediate-density lipoprotein (IDL). Furthermore, statins also decrease the hepatic and endogenous cholesterol production by inhibiting HMG-CoA reductase [43], but they do not affect Lp(a) [145]. Interestingly, it could be demonstrated that statins also have some detrimental effects, for example by increasing the levels of circulating PCSK9 [146].…”

“…They act on the PCSK9 protein itself rather than targeting the gene expression. Additionally, PCSK9 mAb decreases the production rate of hepatic Lp(a) particles [145] on top of increasing the clearance of them [78]. Thus, the use of mAbs have been highly sought out for the treatment of cardiovascular complications.…”