The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

Lebeau, Paul; Wassef, Hanny; Byun, Jae Hyun; Platko, Khrystyna; Ason, Brandon; Jackson, Simon; Dobroff, Joshua; Shetterly, Susan; Richards, William G.; Al‐Hashimi, Ali; Won, Kevin Doyoon; Mbikay, Majambu; Prat, Annik; Tang, An Li; Paré, Guillaume; Pasqualini, Renata; Seidah, Nabil G.; Arap, Wadih; Chrétien, Michel; Austin, Richard C.

doi:10.1172/jci128650

Cited by 30 publications

(47 citation statements)

References 50 publications

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“…PCSK9 missense mutant R46L, L253F and A443T carriers all exhibited low LDL levels, while hepatic triglycerides were normal [156]. Individuals with the loss-offunction PCSK9 Q152H variant had normal liver function [157]. Based on these results, it appears that PCSK9 genotypes modify NAFLD pathogenesis only in some patients.…”

Section: Pcsk9 and Nafld Pathogenesismentioning

confidence: 86%

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Grewal

Buechler

2022

IJMS

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Chronic liver diseases are commonly associated with dysregulated cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease of the proprotein convertase family that is mainly synthetized and secreted by the liver, and represents one of the key regulators of circulating low-density lipoprotein (LDL) cholesterol levels. Its ability to bind and induce LDL-receptor degradation, in particular in the liver, increases circulating LDL-cholesterol levels in the blood. Hence, inhibition of PCSK9 has become a very potent tool for the treatment of hypercholesterolemia. Besides PCSK9 limiting entry of LDL-derived cholesterol, affecting multiple cholesterol-related functions in cells, more recent studies have associated PCSK9 with various other cellular processes, including inflammation, fatty acid metabolism, cancerogenesis and visceral adiposity. It is increasingly becoming evident that additional roles for PCSK9 beyond cholesterol homeostasis are crucial for liver physiology in health and disease, often contributing to pathophysiology. This review will summarize studies analyzing circulating and hepatic PCSK9 levels in patients with chronic liver diseases. The factors affecting PCSK9 levels in the circulation and in hepatocytes, clinically relevant studies and the pathophysiological role of PCSK9 in chronic liver injury are discussed.

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Section: Pcsk9 and Nafld Pathogenesismentioning

confidence: 86%

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Grewal

Buechler

2022

IJMS

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“…Asp301Gly [27] Mutation in Exon 6 that leads to amino acid change of D301G and thereby to a lack of circulating PCSK9 PCSK9-679X [97] Elimination of final cysteine in the C-terminal domain that leads to PCSK9 failing to exit the ER after the protein folding is disrupted PCSK9-FS [24] C-terminal frameshift by which PCSK9 fails to exit the ER Q152H (Gln152His) [24,128,129] Amino acid substitution that prevents the autocatalytic processing of proPCSK9 inducing the reduction in circulating levels of PCSK9 and LDL-C, reduction in risk of developing CVD R434W [103] Alteration in the hinge region that impedes PCSK9 retention in the Trans-Golgi network that causes lower secretion levels of PCSK9 rs11206510 [130][131][132] rs11583680 (A53V) [133] rs2479409 [134] rs151193009 (R93C) [100,134] SNPs which lead to reduced risk of CAD, peripheral artery disease, abdominal aortic aneurysm, type 2 diabetes, ischemic stroke, dementia, chronic obstructive pulmonary artery disease and cancer rs11591147 (R46L) [126] GT/TT genotype in exon 1 that leads to decreased levels of LDL-C and reduced risk of CVDs S127R [118] Mutation in pro-domain that causes low binding affinity to LDLR and increased catabolism of LDLC S386A [126] R237W [126] Point mutations in the catalytic domain that lead to the failure of PCSK9 to undergo autocatalytic cleavage Table 2. Gain-of-function mutations.…”

Section: Name Of Mutation + Reference Cause and Consequencesmentioning

confidence: 99%

PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology

2021

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Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is secreted mostly by hepatocytes and to a lesser extent by the intestine, pancreas, kidney, adipose tissue, and vascular cells. PCSK9 has been known to interact with the low-density lipoprotein receptor (LDLR) and chaperones the receptor to its degradation. In this manner, targeting PCSK9 is a novel attractive approach to reduce hyperlipidaemia and the risk for cardiovascular diseases. Recently, it has been recognised that the effects of PCSK9 in relation to cardiovascular complications are not only LDLR related, but that various LDLR-independent pathways and processes are also influenced. In this review, the various LDLR dependent and especially independent effects of PCSK9 on the cardiovascular system are discussed, followed by an overview of related PCSK9-polymorphisms and currently available and future therapeutic approaches to manipulate PCSK9 expression.

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“…Of interest was the ER chaperon GRP78, which worked as an antiviral for HAV [ 12 , 13 , 31 ]. ER stress is an important factor in hepatic cell damage, which is induced by an innate immune response, including TLR signaling pathways [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication

Sasaki

Masuzaki

Matsumoto

et al. 2021

IJMS

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Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-β production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection.

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The loss-of-function PCSK9Q152H variant increases ER chaperones GRP78 and GRP94 and protects against liver injury

Abstract: The human PCSK9 Q152H variant acquires an unexpected co-chaperone function that increases the expression of GRP78 and GRP94 to protect against ER stress and liver injury.

Cited by 30 publications

References 50 publications

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

Emerging Insights on the Diverse Roles of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in Chronic Liver Diseases: Cholesterol Metabolism and Beyond

PCSK9: A Multi-Faceted Protein That Is Involved in Cardiovascular Biology

Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication

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