Inclisiran
Cholesterol Lowering Drugs

Author: Gianpiero Pescarmona
Date: 28/03/2023

Description

Inclisiran is a small interfering RNA that acts as an inhibitor of a proprotein convertase, specifically, inhibiting translation of the protein termed proprotein convertase subtilisin/kexin type 9 (PCSK9).8[12]13[4] Small interfering RNA molecules (siRNAs) are designed to intervene in the pathway of RNA interference (RNAi), a naturally operating mechanism, wherein they bind to a complex within the cell termed the RNA-induced silencing complex (RISC); after binding, the RISC structure in the siRNA-RISC complex is altered, allowing it to cleave specific messenger RNA molecules (mRNAs).8 The siRNA-RISC complex is catalytic, and thus can cleave multiple copies of the mRNA that it targets; cleaved mRNAs are not translated into proteins, and thus the concentration of the protein targeted by the siRNA design is decreased.8

The proprotein convertase, PCSK9, is a liver-produced and -secreted serine protease whose binding and action on LDL receptors results in their increased lysosomal degradation in hepatocytes, a consequence of which is an increase in the level of circulating LDL cholesterol (and inhibition of which, the decrease in this level).

PCSK9+AND+insulin

Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c, 2006(19)57975-3/fulltext

PCSK9 acts as a natural inhibitor of the low density lipoprotein receptor pathway, and both genes are regulated by depletion of cholesterol cell content (hypothyroidism!!!) and statins, via sterol regulatory element-binding protein (SREBP).

PCSK9 is expressed in human visceral adipose tissue and regulated by insulin and cardiac natriuretic peptides, 2019

PCSK9 and LDLR regulation in human adipocytes. We studied PCSK9 and LDLR regulation
by insulin, atrial natriuretic peptide (ANP, a potent lipolytic agonist that antagonizes insulin),

PCSK9+AND+thyroid

Thyroid stimulating hormone exhibits the impact on LDLR/LDL-c via up-regulating hepatic PCSK9 expression, 2017

… human thyroid stimulating hormone (rhTSH) stimulated PCSK9 mRNA expression in a dose
dependent manner (A), and 25 ng/ml rhTSH increased the mRNA levels of PCSK9 both after …

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