Review

Advances in study of PCSK9 inhibitors in treatment of non-alcoholic fatty liver disease

Expand
  • Endocrine and Diabetes Center, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Traditional Chinese Medicine, Jiangsu Branch of China Academy of Chinese Medical Science,Nanjing 210028,China

Received date: 2023-09-04

  Online published: 2024-07-08

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the chronic liver disease with the highest incidence rate, and its main cause is due to disorders of lipid metabolism and damage to the liver caused by ectopic fat deposition. Proprotein convertase bacillus subtilis/ kexin type 9 (PCSK9), as a lipid-regulating protease in vivo, plays a key role in abnormal lipid metabolism. Dyslipidemia levels can be significantly improved by inhibiting PCSK9 binding to receptors circulating in vivo. Therefore, PCSK9 inhibitors may improve the condition of NAFLD patients and achieve therapeutic effects.

Cite this article

SHEN Yun, XU Yijiao, WEI Xiao, ZHANG Ruixiang, LIU Chao . Advances in study of PCSK9 inhibitors in treatment of non-alcoholic fatty liver disease[J]. Journal of Internal Medicine Concepts & Practice, 2024 , 19(02) : 136 -139 . DOI: 10.16138/j.1673-6087.2024.02.09

References

[1] Bugianesi E, Petta S. NAFLD/NASH[J]. J Hepatol, 2022, 77(2):549-550.
[2] Stefan N, Cusi K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes[J]. Lancet Diabetes Endocrinol, 2022, 10(4):284-296.
[3] Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease[J]. Annu Rev Pathol, 2018,13:321-350.
[4] Kechagias S, Ekstedt M, Simonsson C, et al. Non-invasive diagnosis and staging of non-alcoholic fatty liver disease[J]. HHormones (Athens), 2022, 21(3):349-368.
[5] Nobili V, Svegliati-Baroni G, Alisi A, et al. A 360-degree overview of paediatric NAFLD[J]. J Hepatol, 2013, 58(6):1218-1229.
[6] Theocharidou E, Papademetriou M, Reklou A, et al. The role of PCSK9 in the pathogenesis of non-alcoholic fatty liver disease and the effect of PCSK9 inhibitors[J]. Curr Pharm Des, 2018, 24(31):3654-3657.
[7] Liu F, Zhu X, Jiang X, et al. Transcriptional control by HNF-1: emerging evidence showing its role in lipid metabolism and lipid metabolism disorders[J]. Genes Dis, 2021, 9(5):1248-1257.
[8] Wiciński M, ?ak J, Malinowski B, et al. PCSK9 signaling pathways and their potential importance in clinical practice[J]. EPMA J, 2017, 8(4):391-402.
[9] Malig?ówka M, Kosowski M, Hachu?a M, et al. Insight into the evolving role of PCSK9[J]. Metabolites, 2022, 12(3):256.
[10] Nassoury N, Blasiole DA, Tebon Oler A, et al. The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR[J]. Traffic, 2007, 8(6):718-732.
[11] Ruscica M, Ferri N, Macchi C, et al. Liver fat accumulation is associated with circulating PCSK9[J]. Ann Med, 2016, 48(5):384-391.
[12] Stoekenbroek RM, Lambert G, Cariou B, et al. Inhibiting PCSK9 - biology beyond LDL control[J]. Nat Rev Endocrinol, 2018, 15(1):52-62.
[13] Lin XL, Xiao LL, Tang ZH, et al. Role of PCSK9 in lipid metabolism and atherosclerosis[J]. Biomed Pharmacother, 2018,104:36-44.
[14] Wargny M, Ducluzeau PH, Petit JM, et al. Circulating PCSK9 levels are not associated with the severity of hepatic steatosis and NASH in a high-risk population[J]. Atherosclerosis, 2018,278:82-90.
[15] Emma MR, Giannitrapani L, Cabibi D, et al. Hepatic and circulating levels of PCSK9 in morbidly obese patients: Relation with severity of liver steatosis[J]. Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865(12):158792.
[16] Sabatine MS. PCSK9 inhibitors: clinical evidence and implementation[J]. Nat Rev Cardiol, 2019, 16(3):155-165.
[17] Cariou B, Langhi C, Le Bras M, et al. Plasma PCSK9 concentrations during an oral fat load and after short term high-fat, high-fat high-protein and high-fructose diets[J]. Nutr Metab (Lond), 2013, 10(1):4.
[18] Baragetti A, Balzarotti G, Grigore L, et al. PCSK9 deficiency results in increased ectopic fat accumulation in experimental models and in humans[J]. Eur J Prev Cardiol, 2017, 24(17):1870-1877.
[19] Lebeau P, Al-Hashimi A, Sood S, et al. Endoplasmic reticulum stress and Ca2+ depletion differentially modulate the sterol regulatory protein PCSK9 to control lipid metabolism[J]. J Biol Chem, 2017, 292(4):1510-1523.
[20] Mastrototaro L, Roden M. Insulin resistance and insulin sensitizing agents[J]. Metabolism, 2021,125:154892.
[21] Sakurai Y, Kubota N, Yamauchi T, et al. Role of insulin resistance in MAFLD[J]. Int J Mol Sci, 2021, 22(8):4156.
[22] Miao J, Manthena PV, Haas ME, et al. Role of insulin in the regulation of proprotein convertase subtilisin/kexin type 9[J]. Arterioscler Thromb Vasc Bio, 2015, 35(7):1589-1596.
[23] Shimomura I, Matsuda M, Hammer RE, et al. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice[J]. Mol Cell, 2000, 6(1):77-86.
[24] Da Dalt L, Ruscica M, Bonacina F, et al. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor[J]. Eur Heart J, 2019, 40(4):357-368.
[25] Paquette M, Gauthier D, Chamberland A, et al. Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis[J]. Clin Biochem, 2020,77:20-25.
[26] Schuck S, Prinz WA, Thorn KS, et al. Correction: membrane expansion alleviates endoplasmic reticulum stress independently of the unfolded protein response[J]. J Cell Biol, 2021, 220(4):jcb.20090707402092021c.
[27] Wargny M, Ducluzeau PH, Petit JM, et al. Circulating PCSK9 levels are not associated with the severity of hepatic steatosis and NASH in a high-risk population[J]. Atherosclerosis, 2018,278:82-90.
[28] Shafiq M, Walmann T, Nutalapati V, et al. Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver[J]. World J Hepatol, 2020, 12(12):1258-1266.
[29] Marjot T, Moolla A, Cobbold JF, et al. Nonalcoholic fatty liver disease in adults: current concepts in etiology, outcomes, and management[J]. Endocr Rev, 2020, 41(1):bnz009.
[30] Momtazi-Borojeni AA, Banach M, Ruscica M, et al. The role of PCSK9 in NAFLD/NASH and therapeutic implications of PCSK9 inhibition[J]. Expert Rev Clin Pharmacol, 2022, 15(10):1199-1208.
[31] Amput P, Palee S, Arunsak B, et al. PCSK9 inhibitor effectively attenuates cardiometabolic impairment in obese-insulin resistant rats[J]. Eur J Pharmacol. 2020 Sep 15;883:173347.
[32] He Y, Rodrigues RM, Wang X, et al. Neutrophil-to-hepatocyte communication via LDLR-dependent miR-223-enriched extracellular vesicle transfer ameliorates non-alcoholic steatohepatitis[J]. J Clin Invest, 2021, 131(3):e141513.
[33] Ioannou GN, Lee SP, Linsley PS, et al. PCSK9 deletion promotes murine nonalcoholic steatohepatitis and hepatic carcinogenesis[J]. Hepatol Commun, 2022, 6(4):780-794.
[34] Xiao X, Luo Y, Peng D. Updated understanding of the crosstalk between glucose/insulin and cholesterol metabolism[J]. Front Cardiovasc Med, 2022, 9:879355.
[35] Sakurai Y, Kubota N, Yamauchi T, et al. Role of insulin resistance in MAFLD[J]. Int J Mol Sci, 2021, 22(8):4156.
[36] Shafiq M, Walmann T, Nutalapati V, et al. Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver[J]. World J Hepatol, 2020, 12(12):1258-1266.
[37] Khan SU, Yedlapati SH, Lone AN, et al. PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis[J]. BMJ, 2022,377:e069116.
Outlines

/