IL-1 Family Cytokine Pathways Underlying NAFLD: Towards New Treatment Strategies

Mirea, Andreea-Manuela; Tack, Cees J.; Chavakis, Triantafyllos; Joosten, Leo A. B.; Toonen, Erik J. M.

doi:10.1016/j.molmed.2018.03.005

Cited by 109 publications

(91 citation statements)

References 69 publications

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“…The clinical relevance of low-grade inflammation in the pathogenesis of CVD has recently been demonstrated unequivocally by the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS), in which treatment with canakinumab, a monoclonal antibody targeting IL-1β, reduced recurrent CVD events independent of lipid lowering [23]. Of interest, IL-1β also plays an active role in the pathogenesis of NASH in different animal models [24]. It is not known, however, whether IL-1β mediates the association between NASH and CVD.…”

Section: Potential Mediators Of the Association Between Nafld And Cvdmentioning

confidence: 99%

Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

et al. 2019

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Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

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Section: Potential Mediators Of the Association Between Nafld And Cvdmentioning

confidence: 99%

Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

et al. 2019

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“…Not only cytokines, but a variety of other markers have been evaluated in liver diseases including liver enzymes, matrix components, or caspase-cleaved K18 fragments (M30) [29,56]. In NAFLD, an extensive body of literature has also looked at cytokines [18,25,31]. In our study, several cytokines did not show significant differences between NAFLD and NL patients.…”

Section: Discussionmentioning

confidence: 57%

“…Pro-and anti-inflammatory cytokines involved in the physiopathology of NAFLD progression. IL-1β promotes fat accumulation in hepatocytes and then, it induces liver inflammation and stimulates liver fibrosis in a late stage of the disease [21,31]; TGF-β performs the same function [29]. TNF-α mediates the early stage of NAFLD by fat accumulation in hepatocytes and also facilitates disease progression to a more advanced stage.…”

Section: Introductionmentioning

confidence: 99%

Relationship between IL-8 Circulating Levels and TLR2 Hepatic Expression in Women with Morbid Obesity and Nonalcoholic Steatohepatitis

Auguet

Bertran

Binetti

et al. 2020

IJMS

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The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess the relationship between circulating levels of cytokines, hepatic expression of toll-like receptors (TLRs), and degrees of NAFLD, and to investigate whether these levels could serve as noninvasive biomarkers of NASH. The present study assessed plasma levels of cytokines in 29 normal-weight women and 82 women with morbid obesity (MO) (subclassified: normal liver (n = 29), simple steatosis (n = 32), and NASH (n = 21)). We used enzyme-linked immunosorbent assays (ELISAs) to quantify cytokine and TLR4 levels and RTqPCR to assess TLRs hepatic expression. IL-1β, IL-8, IL-10, TNF-α, tPAI-1, and MCP-1 levels were increased, and adiponectin levels were decreased in women with MO. IL-8 was significantly higher in MO with NASH than in NL. To sum up, high levels of IL-8 were associated with the diagnosis of NASH in a cohort of women with morbid obesity. Moreover, a positive correlation between TLR2 hepatic expression and IL-8 circulating levels was found.

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“…This IL has recently been implicated in the development and progression of chronic liver disease 17,46,47 . A variety of triggers has been shown to increase hepatic IL‐1 production through both inflammasome‐dependent and independent pathways, causing inflammation, pyroptosis and collagen deposition 20,48,49 . To further strengthen the pivotal role of IL‐1 in liver disease, inhibition of IL‐1 signalling has led to slowing and reversal of liver injury in murine models 20,50 .…”

Section: Discussionmentioning

confidence: 99%

Non‐amyloid liver involvement in familial Mediterranean fever: A systematic literature review

Fraisse

Savey

Hentgen

et al. 2020

Liver International

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Introduction: Familial Mediterranean fever (FMF), the most frequent autoinflammatory disease, is caused by mutations in the MEFV gene. It is characterized by recurrent febrile attacks of polyserositis. Liver abnormalities may develop during its course, but they remain poorly defined.Objective: To describe liver involvement in FMF patients. Methods:A systematic search was conducted through PubMed/Medline and Embase from 1946 to January 2020. All articles describing children and adults with FMF and liver involvement were included. Patients with amyloidosis were excluded. The selected full-text articles were independently reviewed by three investigators.Results: Forty-three articles were identified, of which 20 articles with a total of 99 patients were included: 74 adults, 23 children and two patients of unknown age. Ten patients had cryptogenic cirrhosis, 48 had nonalcoholic fatty liver disease (NAFLD), four had Budd-Chiari syndrome (BCS), 12 had isolated hyperbilirubinaemia and 25 had elevated liver enzymes. Conclusion:Despite a low prevalence of metabolic risk factors, FMF may be associated with NAFLD and cryptogenic cirrhosis as a consequence of chronic or recurrent inflammation. FMF patients should be regularly screened for liver injury. The latter may be prevented and treated by daily colchicine intake. The evidence was insufficient to establish an association with BCS, hyperbilirubinaemia or autoimmune hepatitis. K E Y W O R D Scolchicine, cytolysis, familial Mediterranean fever, inflammation, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis

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IL-1 Family Cytokine Pathways Underlying NAFLD: Towards New Treatment Strategies

Cited by 109 publications

References 69 publications

Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

Relationship between IL-8 Circulating Levels and TLR2 Hepatic Expression in Women with Morbid Obesity and Nonalcoholic Steatohepatitis

Non‐amyloid liver involvement in familial Mediterranean fever: A systematic literature review

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