Effects of PCSK-9 Inhibition by Alirocumab Treatments on Biliary Cirrhotic Rats

• Published in: International journal of molecular sciences Vol. 23; no. 13; p. 7378
• Main Authors: Huang, Hui-Chun, Hsu, Shao-Jung, Chang, Ching-Chih, Chuang, Chiao-Lin, Hou, Ming-Chih, Lee, Fa-Yauh
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 02.07.2022; MDPI
• Subjects: Ammonia; Angiogenesis; Antioxidants; Bile ducts; Biochemistry; Cholesterol; Fibrosis; Hemodynamics; Hepatic encephalopathy; Hyperlipidemia; Hypertension; Inflammation; Kexin; Lipids; Liver; Liver cirrhosis; Low density lipoprotein; Low density lipoprotein receptors; Markers; Mesentery; Monoclonal antibodies; Mortality; Oxidants; Oxidative stress; oxidized low-density lipoprotein; Oxidizing agents; PCSK9 inhibitor; Plasma; Plasma levels; Proprotein convertases; Rodents; Subtilisin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23137378

Hyperlipidemia and oxidative stress with elevated oxidized low-density lipoprotein (ox-LDL) exacerbate hepatic inflammation and fibrosis. The plasma level of low-density lipoprotein (LDL) is controlled by proprotein convertase subtilisin/kexin 9 (PCSK9). Alirocumab is a monoclonal antibody that decreases LDL via inhibiting PCSK9 function. Apart from lipid-lowering effects, alirocumab exerts anti-inflammation, anti-angiogenesis and anti-oxidant effects. This study aims to investigate the impact of alirocumab treatment on common bile duct ligation (BDL)-induced biliary cirrhotic rats. After a 4-week treatment of alirocumab, the hemodynamic data, blood biochemistry, ox-LDL level, oxidative stress markers, severity of hepatic encephalopathy and abnormal angiogenesis of BDL rats were measured and compared to the control group. BDL rats presented cirrhotic pictures and elevated ammonia, total cholesterol, LDL and ox-LDL levels compared to the control group. Alirocumab decreased plasma levels of total cholesterol, LDL, and oxidative stress markers; however, it did not affect the hemodynamics, liver and renal biochemistry, and the plasma levels of ammonia and ox-LDL. The motor activities, portal-systemic collaterals and mesenteric vascular density were not significantly different between alirocumab-treated and control groups. In addition, it did not affect hepatic inflammation, intrahepatic angiogenesis, liver fibrosis and free cholesterol accumulation in the liver of BDL rats. In conclusion, PCSK9 inhibition by alirocumab treatment ameliorates hyperlipidemia and systemic oxidative stress in biliary cirrhotic rats. However, it does not affect the plasma level of ox-LDL, intrahepatic inflammation and fibrosis. In addition, PCSK9 inhibition has a neutral effect on abnormal angiogenesis and hepatic encephalopathy in biliary cirrhotic rats.