PCSK9 inhibition as a novel therapeutic target for alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) causes significant morbidity and mortality, and pharmacological treatment options are limited. In this study, we evaluated the PCSK9 inhibitor alirocumab, a monoclonal antibody that robustly reduces low-density lipoprotein cholesterol (LDL-C), for the treatment of ALD using a rat model of chronic alcohol exposure. Alirocumab (50 mg/kg) or vehicle was administered weekly for 6 weeks to rats receiving a 12% alcohol liquid diet or an isocaloric control diet. At the end of the alcohol exposure protocol, serum and liver samples were obtained for molecular characterization and histopathological analysis. PCSK9 inhibition with alirocumab attenuated alcohol-induced hepatic triglyceride accumulation through regulation of lipid metabolism (mRNA expression of modulators of fatty acid synthesis (FAS) and catabolism (PPARα and CPT1)), hepatocellular injury (ALT), hepatic inflammation (mRNA expression of pro-inflammatory cytokines/chemokines (TNFa, IL-1β, IL-22, IL-33, IL-17α, IL-2, MIP-2, and MCP-1), and neutrophil infiltration (myeloperoxidase staining)). Alirocumab treatment also attenuated alcohol-induced PCSK9 mRNA elevation and upregulated LDL-receptor (LDL-R) via modulation of the transcription factors (SREBP-1, SREBP-2, and E2F1) in liver. We demonstrated that chronic anti-PCSK9 treatment using the monoclonal antibody alirocumab attenuated alcohol-induced steatohepatitis in the rat model. Given the large unmet clinical need for effective and novel treatments for ALD, anti-PCSK9 treatment with the monoclonal antibody that spares liver metabolism is a viable new therapeutic possibility. Future studies are needed to elucidate the exact role of PCSK9 in ALD and alcohol use disorder (AUD) and to evaluate efficacy and safety of anti-PCSK9 treatment in clinical populations with ALD/AUD.

Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223–enriched extracellular vesicle transfer ameliorates nonalcoholic steatohepatitis

“…The PCSK9 inhibitor, which upregulates LDLR, is currently being used as the second line treatment of hypercholesterolemia (52). Interestingly, treatment with PCSK9 inhibitor has been shown to ameliorate alcoholic fatty liver disease (53) and PCSK9 may be involved in NAFLD development in experimental models and patients (54). Although these beneficial effects may be partially attributed to the reduction of cholesterol, the present findings suggest that PCSK9 inhibition can ameliorate NAFLD via a mechanism independent of LDL cholesterol reduction, by enhancing the LDLR-dependent miR-223enriched EV uptake by hepatocytes which then inhibits liver inflammation and fibrosis.…”

Alcohol and Pain: A Translational Review of Preclinical and Clinical Findings to Inform Future Treatment Strategies

“…There are no standardized procedures for the alcohol liquid diet across laboratories, and the concentration of alcohol in the diet varies considerably (e.g., 5 to 35%). However, this unique approach results in BALs that are sufficient to induce liver damage, intoxication, tolerance, dependence, and withdrawal (Gilpin et al, ; Lee et al, in press). Equally effective in producing alcohol dependence is the chronic, intermittent alcohol vapor exposure model, where animals are typically exposed to alcohol vapor for 14 h/d (intoxication), followed by 10 hours with vapor off (withdrawal).…”

PCSK9: A Potential Therapeutic Target for Sepsis

“…In animal models, LPS could regulate the expression of PCSK9 mRNA [ 43 ]. Interestingly, in a recent study, significant elevation was found in PCSK9 and inflammatory factors in the rat model of alcohol liver disease, whereas there was a significant inhibition of inflammatory reaction after administration of anti-PCSK9 agents [ 44 ]. Thereby, it was proposed that PCSK9 may directly trigger the inflammatory reactions in the pathogenesis of alcohol liver disease.…”