PCSK9 is a critical regulator of the innate immune response and septic shock outcome

Walley, Keith R.; Thain, Katherine R.; Russell, James A.; Reilly, Muredach P.; Meyer, Nuala J.; Ferguson, Jane F.; Christie, Jason D.; Nakada, Taka‐aki; Fjell, Christopher D.; Thair, Simone A.; Cirstea, Mihai; Boyd, John H.

doi:10.1126/scitranslmed.3008782

Cited by 304 publications

(404 citation statements)

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“…Hepatic steatosis contributes to augmented hepatic ER stress, mitochondrial dysfunction and insulin resistance (24,25). Moreover, it may impair the hepatic clearance of LPS (26). As shown in the current animal study and in other clinical observations (17,27), LPS strongly activates lipolysis in WAT, which could instigate a vicious positive feedback loop between WAT lipolysis, hepatic lipid accumulation and hepatic LPS clearance.…”

Section: Discussionmentioning

confidence: 72%

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Patsouris

Sadri

et al. 2015

Mol Med

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Extensively burned patients often suffer from sepsis, a complication that enhances postburn hypermetabolism and contributes to increased incidence of multiple organ failure, morbidity and mortality. Despite the clinical importance of burn sepsis, the molecular and cellular mechanisms of such infection-related metabolic derangements and organ dysfunction are still largely unknown. We recently found that upon endoplasmic reticulum (ER) stress, the white adipose tissue (WAT) interacts with the liver via inflammatory and metabolic signals leading to profound hepatic alterations, including hepatocyte apoptosis and hepatic fatty infiltration. We therefore hypothesized that burn plus infection causes an increase in lipolysis of WAT after major burn, partially through induction of ER stress, contributing to hyperlipidemia and profound hepatic lipid infiltration. We used a two-hit rat model of 60% total body surface area scald burn, followed by intraperitoneal (IP) injection of Pseudomonas Aeruginosa-derived lipopolysaccharide (LPS) 3 d postburn. One day later, animals were euthanized and liver and epididymal WAT (EWAT) samples were collected for gene expression, protein analysis and histological study of inflammasome activation, ER stress, apoptosis and lipid metabolism. Our results showed that burn plus LPS profoundly increased lipolysis in WAT associated with significantly increased hepatic lipid infiltration. Burn plus LPS augmented ER stress by upregulating CHOP and activating ATF6, inducing NLRP3 inflammasome activation and leading to increased apoptosis and lipolysis in WAT with a distinct enzymatic mechanism related to inhibition of AMPK signaling. In conclusion, burn sepsis causes profound alterations in WAT and liver that are associated with changes in organ function and structure.

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Section: Discussionmentioning

confidence: 72%

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Patsouris

Sadri

et al. 2015

Mol Med

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“…An interesting alternative is to target the organism to reduce inflammation. Proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors lower low density lipoprotein (LDL) levels and may also increase clearance of pathogen lipids, such as LPS, transported in LDL [92]. This novel therapeutic strategy requires further basic and clinical trial investigations.…”

Section: Novel Anti-inflammatory Therapiesmentioning

confidence: 99%

The intensive care medicine research agenda on septic shock

et al. 2017

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“…PCtargeted therapies are foreseeable in the near future, most imminent among them being the treatment of hypercholesterolemia and cardiovascular with inhibitors of PCSK9 (Wu et al 2015). Anti-PCSK9 therapies may also be applicable to infectious diseases as suggested by the resistance to bacterial septic shock of carriers of hypocholesterolemic mutations in its gene (Walley et al 2014).…”

Section: Importance Of the Pcs In Human Biologymentioning

confidence: 99%

60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9)

Chrétien

Mbikay

2016

Journal of Molecular Endocrinology

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Pro-opiomelanocortin (POMC), is a polyprotein expressed in the pituitary and the brain where it is proteolytically processed into peptide hormones and neuropeptides with distinct biological activities. It is the prototype of multipotent prohormones. The prohormone theory was first suggested in 1967 when Chrétien and Li discovered γ-lipotropin and observed that (i) it was part of β-lipotropin (β-LPH), a larger polypeptide characterized 2 years earlier and (ii) its C-terminus was β-melanocyte-stimulating hormone (β-MSH). This discovery led them to propose that the lipotropins might be related biosynthetically to the biologically active β-MSH in a precursor to end product relationship. The theory was widely confirmed in subsequent years. As we celebrate the 50th anniversary of the sequencing of β-LPH, we reflect over the lessons learned from the sequencing of those proteins; we explain their extension to the larger POMC precursor; we examine how the theory of precursor endoproteolysis they inspired became relevant for vast fields in biology; and how it led, after a long and arduous search, to the novel proteolytic enzymes called proprotein convertases. This family of nine enzymes plays multifaceted functions in growth, development, metabolism, endocrine, and brain functions. Their genetics has provided many insights into health and disease. Their therapeutic targeting is foreseeable in the near future. Thus, what started five decades ago as a theory based on POMC fragments, has opened up novel and productive avenues of biological and medical research, including, for our own current interest, a highly intriguing hypocholesterolemic Gln152His PCSK9 mutation in French-Canadian families.

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PCSK9 is a critical regulator of the innate immune response and septic shock outcome

Cited by 304 publications

References 50 publications

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

Alternative Mechanism for White Adipose Tissue Lipolysis after Thermal Injury

The intensive care medicine research agenda on septic shock

60 YEARS OF POMC: From the prohormone theory to pro-opiomelanocortin and to proprotein convertases (PCSK1 to PCSK9)

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