PCSK9 and resistin at the crossroads of the atherogenic dyslipidemia

Abstract

The atherogenic dyslipidemia is a pathophysiological lipid triad, composed of high triglycerides and low-density lipoprotein and low high-density lipoprotein. The dyslipidemia is highly prevalent in individuals who are obese, insulin resistant and those with Type 2 diabetes and is the major contributing factor to the high atherosclerotic cardiovascular disease risk in these subjects. The primary initiating event in atherogenic dyslipidemia development is the hepatic overproduction of very-low-density lipoprotein (VLDL). The intracellular and extracellular protein triggers of hepatic VLDL production were not known until the recent identification of the causal roles of PCSK9 and resistin. Both PCSK9 and resistin act in large part by targeting and reducing the hepatic degradation of VLDL apoB through distinctly different mechanisms. In the current review, we discuss both the individual roles and the interaction of these proteins in driving atherogenic dyslipidemia, and thus, atherosclerotic cardiovascular disease progression in humans. We further explore the important therapeutic implications of these findings.

Keywords::

• atherogenic dyslipidemia
• atherosclerotic cardiovascular diseases
• PCSK9
• resistin
• triglycerides
• VLDL

Financial & competing interests disclosure

S Rashid has received research support from Merck and Co. and AstraZeneca. JJP Kastelein is a consultant to a number of biotechnology and pharmaceutical companies that develop compounds in the ASCVD therapeutics area (AstraZeneca, MSD, Sanofi-Aventis, Regeneron and AMT). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • The atherogenic dyslipidemia is the main lipid and lipoprotein impairment in individuals who are obese, insulin resistant and subjects with Type 2 diabetes and is the major cause of their elevated risk of development of atherosclerotic cardiovascular diseases (ASCVD).

• • Hepatic very-low-density lipoprotein (VLDL) overproduction is the primary lipoprotein abnormality that drives the development of each component of the atherogenic dyslipidemia – elevated serum triglycerides, high low-density lipoprotein (LDL) and apoB levels and low high-density lipoprotein cholesterol (HDL-C).

• • PCSK9 and resistin are novel hepatic intracellular and extracellular triggers of hepatic VLDL production, respectively.

• • PCSK9 stimulates hepatic VLDL overproduction by reducing the degradation of the major protein constituent of VLDL particles, apoB, in the liver, through via both LDL receptor-dependent apoB degradation pathways and LDL receptor-independent pathways.

• • Resistin stimulates hepatic VLDL overproduction by reducing hepatic VLDL apoB degradation through increasing the activity of the rate-limiting enzyme in VLDL assembly, microsomal triglyceride transfer protein (MTP), and through decreasing the activity of the insulin signaling pathway.

• • VLDL remnants have been shown to be directly involved in increasing coronary artery atherosclerosis progression and makers of circulating VLDL levels are significantly and independently associated with ASCVD risk.

• • There are few clinically effective triglyceride-lowering therapies currently available and the evidence ascertaining their protection from ASCVD risk has been difficult to evaluate; this supports the need for novel targeted VLDL-lowering therapies.

• • Since individuals with loss-of-function mutations in the PCSK9 gene do not show excess hepatic triglyceride accumulation or steatosis along with their decline in serum triglycerides, liver targeted PCSK9 inhibitory approaches may be less likely to lead to off-target fatty liver effects and liver toxicity seen with other hepatic VLDL apoB targeted therapeutic approaches.

• • Therapies targeted at inhibiting PCSK9 within the liver, and resistin itself within the adipocyte or its receptor within the hepatocyte, and their metabolic effects on VLDL, hold great potential in lowering triglyceride and apoB levels, as well as ASCVD, in individuals with the atherogenic dyslipidemia, and should be developed.

Notes