Hormonal influences on cholesterol and bile acid metabolism : focusing on involvement of PCSK9

Elevated plasma LDL-C is today considered a causative factor for the development of atherosclerosis. Increased plasma LDL-C levels are mainly due to reduced numbers of functional LDL receptors (LDLRs) in the liver. PCSK9 and IDOL, are two, recently identified key regulators of cholesterol metabolism, both reducing LDLR numbers in the liver and peripheral tissue thereby increasing plasma LDL-C levels. Several hormones such as estrogen, testosterone and ACTH are known to influence lipoprotein metabolism. In addition, bile acids such as CDCA have been reported to modulate cholesterol metabolism. However, little is known about the underlying mechanisms behind these effects.

In this study, we investigated how natural changes of the endogenous levels of estrogen and how treatments with testosterone, ACTH, and with the natural FXR agonist (CDCA) influence cholesterol metabolism, with a particular focus on the role of PCSK9. It is concluded that:

1) The natural changes of estrogen levels during the menstrual cycle correlate to the concomitant changes observed in circulating levels of PCSK9 and LDL-C. Further, after menopause PCSK9 levels and plasma LDL-C increase while in ageing men of similar age PSCK9 levels were stable.

2) High dose testosterone treatment reduces PCSK9 levels, indicating that this LDLR modulator is under hormonal control. However, the known gender differences in bile acid and cholesterol synthesis cannot be explained from testosterone levels in human.

3) The adrenal glands are practically devoid of the PCSK9 protein while instead IDOL is expressed. Treatment with ACTH suppresses adrenal IDOL expression contributing to the powerful increase in LDLR number during severe stress. Simultaneously, the number of hepatic LDLRs is reduced through a posttrascriptional increase of PCSK9 protein. This effect is dependent on the presence of intact adrenals, compatible with the concept that a sustained adrenal production of corticosteroids is secured by shunting LDL-C to the adrenals in situations of severe stress.

4) CDCA influences lipid metabolism by reducing plasma clearance of LDL-C. The reduction of circulating PCSK9 by CDCA treatment may counter-balance its effect on hepatic LDLRs and plasma LDL-cholesterol.

List of scientific papers

I. Ghosh M, Gälman C, Rudling M, Angelin B. Influence of physiological changes in endogenous estrogen on circulating PCSK9 and LDL cholesterol. J Lipid Res. 56(2):463-469 (2015).
https://doi.org/10.1194/jlr.M055780

II. Ghosh Laskar M, Beckman L, Laskar A, Gårevik N, Ekström L, Rudling M, Angelin B.Testosterone reduces circulating PCSK9 but does not influence cholesterol or bile acid synthesis in healthy males. [Submitted]

III. Ghosh Laskar M, Angelin B, Rudling M. Differential regulation of LDL receptors by ACTH: posttranscriptional control by PCSK9 in the liver and by IDOL in the adrenals. [Manuscript]

IV. Ghosh Laskar M, Eriksson M, Rudling M, Angelin B. Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL while decreasing circulating PCSK9, Lp(a), and apo C-III. J Intern Med. 281(6):575-585 (2017).
https://doi.org/10.1111/joim.12594