The role of PCSK9 in NAFLD/NASH and therapeutic implications of PCSK9 inhibition

Momtazi‐Borojeni, Amir Abbas; Banach, Maciej; Ruscica, Massimiliano; Sahebkar, Amirhossein

doi:10.1080/17512433.2022.2132229

Cited by 13 publications

(6 citation statements)

References 121 publications

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“…38,39 The impact of PCSK9 on human liver is a matter of debate as well. 40 Nevertheless, it is an important issue to address, given the widespread use of PCSK9 inhibitors to treat cardiovascular disease. Whether E144K and C378W mutations remain to be protective on livers is worth further investigation.…”

Section: Discussionmentioning

confidence: 99%

New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol

Meng

Liu

Xiao

et al. 2023

ATVB

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BACKGROUND: Lower plasma levels of LDL (low-density lipoprotein) cholesterol (LDL-C) can reduce the risk of atherosclerotic cardiovascular disease. The loss-of-function mutations in PCSK9 (proprotein convertase subtilisin/kexin type 9) have been known to associate with low LDL-C in many human populations. PCSK9 genetic variants in Chinese Uyghurs who are at high risk of atherosclerotic cardiovascular disease due to their dietary habits have not been reported. METHODS: The study involved the whole-exome and target sequencing of college students from Uyghur and other ethnic groups in Xinjiang, China, for the association of PCSK9 loss-of-function mutations with low plasma levels of LDL-C. The mechanisms by which the identified mutations affect the function of PCSK9 were investigated in cultured cells using biochemical and cell assays. The causal effects of the identified PCSK9 mutations on LDL-C levels were verified in mice injected with adeno-associated virus expressing different forms of PCSK9 and fed a high-cholesterol diet. RESULTS: We identified 2 PCSK9 mutations—E144K and C378W—in Chinese Uyghurs with low plasma levels of LDL-C. The E144K and C378W mutations impaired the maturation and secretion of the PCSK9 protein, respectively. Adeno-associated virus–mediated expression of E144K and C378W mutants in Pcsk9 KO (knockout) mice fed a high-cholesterol diet also hampered PCSK9 secretion into the serum, resulting in elevated levels of LDL receptor in the liver and reduced levels of LDL-C in the serum. CONCLUSIONS: Our study shows that E144K and C378W are PCSK9 loss-of-function mutations causing low LDL-C levels in mice and probably in humans as well.

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Section: Discussionmentioning

confidence: 99%

New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol

Meng

Liu

Xiao

et al. 2023

ATVB

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“… 181 , 182 Recent discoveries have underscored the significance of PCSK9 in managing liver lipid balance. 183 …”

Section: The Role Of Pcsk9 In Various Disordersmentioning

confidence: 99%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

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“…[ 38 , 39 ] Recently, PCSK9 has been linked to the severity of liver steatosis and the development of NASH, but the role of PCSK9 in NAFLD remains contentious. [ 40 ] A recent study performed in NAFLD and obese patients after bariatric surgery found that the hepatic expression and circulating concentrations of PCSK9 were associated with the severity of steatosis and were inversely correlated with alanine transaminase (ALT) and aspartate transaminase (AST) levels; however, the study did not find a significant association with inflammation or ballooning. [ 41 ] This supports, in agreement with other studies, the role of PCSK9 in liver fat accumulation and increased cardiovascular risk via increases in circulating cholesterol concentrations, but not in the progression of liver damage.…”

Section: Mechanisms Linking Non-alcoholic Fatty Liver Disease Endothe...mentioning

confidence: 99%

Navigating the Link Between Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis and Cardiometabolic Syndrome

Gato,

García-Fernández,

Gil-Gómez

et al. 2024

Eur Cardiol

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The global prevalence of non-alcoholic fatty liver disease (NAFLD) is nearly 25% and is increasing rapidly. The spectrum of liver damage in NAFLD ranges from simple steatosis to non-alcoholic steatohepatitis, characterised by the presence of lobular inflammation and hepatocyte ballooning degeneration, with or without fibrosis, which can further develop into cirrhosis and hepatocellular carcinoma. Not only is NAFLD a progressive liver disease, but numerous pieces of evidence also point to extrahepatic consequences. Accumulating evidence suggests that patients with NAFLD are also at increased risk of cardiovascular disease (CVD); in fact, CVDs are the most common cause of mortality in patients with NAFLD. Obesity, type 2 diabetes and higher levels of LDL are common risk factors in both NAFLD and CVD; however, how NAFLD affects the development and progression of CVD remains elusive. In this review, we comprehensively summarise current data on the key extrahepatic manifestations of NAFLD, emphasising the possible link between NAFLD and CVD, including the role of proprotein convertase substilisin/kenin type 9, extracellular vesicles, microbiota, and genetic factors.

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The role of PCSK9 in NAFLD/NASH and therapeutic implications of PCSK9 inhibition

Cited by 13 publications

References 121 publications

New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol

New Loss-of-Function Mutations in PCSK9 Reduce Plasma LDL Cholesterol

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Navigating the Link Between Non-alcoholic Fatty Liver Disease/Non-alcoholic Steatohepatitis and Cardiometabolic Syndrome

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