MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat

Musso, Giovanni; Cassader, Maurizio; Michieli, Franco De; Paschetta, Elena; Pinach, Silvia; Saba, Francesca; Bongiovanni, Daria; Framarin, L.; Berrutti, M; Leone, Nicola; Corvisieri, Stefania; Parente, Renato; Molinaro, Federica; Sircana, Antonio; Bo, Simona; Gambino, Roberto

doi:10.1093/hmg/ddx126

Cited by 13 publications

(8 citation statements)

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“…MERTK, the other TAM receptor activated by GAS6 with prominent expression in the liver, has recognized roles in fibrogenesis, inflammation, and hepatoprotection. 22,23 Evident liver deterioration was detected on H&E slides and in transaminase levels in Mertk -/mice after HFD feeding (Figure 8A, B). In parallel, liver samples from HFDfed MERTK-deficient mice displayed a significant elevation in collagen deposition compared with HFD-fed WT mice (Figure 8A).…”

Section: Hfd-induced Liver Inflammation and Fibrosis Is Decreased By Axl Inhibitionmentioning

confidence: 97%

“…Concurrently, messenger RNA (mRNA) expression of MERTK, the other main receptor of GAS6 in the liver, has been associated with liver fibrosis and NASH. 22,23 This scenario suggests a role of GAS6 signaling in NASH development. 24 Our current results reveal that sAXL is increased in all NAFLD stages in human samples, whereas GAS6 and soluble MERTK (sMERTK) are only enhanced in cirrhotic NASH patients.…”

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confidence: 94%

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A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target

Tutusaus

Gregorio

Cucarull

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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GAS6 signaling through AXL receptor contributes to the progression of nonalcoholic steatohepatitis (NASH). Soluble AXL significantly increases both in NASH patients and mouse models. Experimental AXL inhibition by bemcentinib diminishes inflammation and fibrosis, supporting its therapeutic use in NASH.BACKGROUND AND AIMS: GAS6 signaling, through the TAM receptor tyrosine kinases AXL and MERTK, participates in chronic liver pathologies. Here, we addressed GAS6/TAM involvement in Non-Alcoholic SteatoHepatitis (NASH) development.METHODS: GAS6/TAM signaling was analyzed in cultured primary hepatocytes, hepatic stellate cells (HSC) and Kupffer cells (KCs). Axl -/-, Mertk -/and wild-type C57BL/6 mice were fed with Chow, High Fat Choline-Deficient Methionine-Restricted (HFD) or methionine-choline-deficient (MCD) diet. HSC activation, liver inflammation and cytokine/chemokine production were measured by qPCR, mRNA Array analysis, western blotting and ELISA. GAS6, soluble AXL (sAXL) and MERTK (sMERTK) levels were analyzed in control individuals, steatotic and NASH patients. RESULTS:In primary mouse cultures, GAS6 or MERTK activation protected primary hepatocytes against lipid toxicity via AKT/STAT-3 signaling, while bemcentinib (small molecule AXL inhibitor BGB324) blocked AXL-induced fibrogenesis in primary HSCs and cytokine production in LPS-treated KCs. Accordingly; bemcentinib diminished liver inflammation and fibrosis in MCD-and HFD-fed mice. Upregulation of AXL and ADAM10/ADAM17 metalloproteinases increased sAXL in HFD-fed mice. Transcriptome profiling revealed major reduction in fibroticand inflammatory-related genes in HFDfed mice after bemcentinib administration. HFD-fed Mertk -/mice exhibited enhanced NASH, while Axl -/mice were partially protected. In human serum, sAXL levels augmented even at initial stages, whereas GAS6 and sMERTK increased only in cirrhotic NASH patients. In agreement, sAXL increased in HFD-fed mice before fibrosis establishment, while bemcentinib prevented liver fibrosis/inflammation in early NASH.CONCLUSION: AXL signaling, increased in NASH patients, promotes fibrosis in HSCs and inflammation in KCs, while GAS6 protects cultured hepatocytes against lipotoxicity via MERTK. Bemcentinib, by blocking AXL signaling and increasing GAS6 levels, reduces experimental NASH, revealing AXL as an effective therapeutic target for clinical practice.

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Section: Hfd-induced Liver Inflammation and Fibrosis Is Decreased By Axl Inhibitionmentioning

confidence: 97%

mentioning

confidence: 94%

A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target

Tutusaus

Gregorio

Cucarull

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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“…All the included studies were cross-sectional or case-control studies. Patients with NAFLD in 22 studies 9 , 10 , 12 , 15 – 33 were assessed by liver histology, and 5 studies 34 – 38 evaluated NAFLD by ultrasonography. One study did not specifically describe the diagnosis of NAFLD.…”

Section: Resultsmentioning

confidence: 99%

Serum Resistin Levels in Adult Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis

Han¹,

Chen²,

Liu³

et al. 2021

Journal of Clinical and Translational Hepatology

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“…Indeed, in genome-wide association studies, it has been reported that the MERTK locus rs4374383 G > A correlates with decreased hepatic MerTK expression, thus protecting against liver fibrosis in chronic hepatitis C and NAFLD (Patin et al, 2012; Petta et al, 2016). The same G > A variant has been found to be associated with cardio-metabolic derangement and nutritionally induced inflammation and could contribute in this way to liver and cardio-metabolic disease (Musso et al, 2017). Moreover, it has been shown that in human NAFLD specimens, MerTK is mainly expressed in macrophages and HSCs loosely aggregated within inflammatory foci (Petta et al, 2016).…”

Section: Mertk In the Activation Of Anti-inflammatory M2c Macrophagesmentioning

confidence: 99%

Role of Myeloid-Epithelial-Reproductive Tyrosine Kinase and Macrophage Polarization in the Progression of Atherosclerotic Lesions Associated With Nonalcoholic Fatty Liver Disease

et al. 2019

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Recent lines of evidence highlight the involvement of myeloid-epithelial-reproductive tyrosine kinase (MerTK) in metabolic disease associated with liver damage. MerTK is mainly expressed in anti-inflammatory M2 macrophages where it mediates transcriptional changes including suppression of proinflammatory cytokines and enhancement of inflammatory repressors. MerTK is regulated by metabolic pathways through nuclear sensors including LXRs, PPARs, and RXRs, in response to apoptotic bodies or to other sources of cholesterol. Nonalcoholic fatty liver disease (NAFLD) is one of the most serious public health problems worldwide. It is a clinicopathological syndrome closely related to obesity, insulin resistance, and oxidative stress. It includes a spectrum of conditions ranging from simple steatosis, characterized by hepatic fat accumulation with or without inflammation, to nonalcoholic steatohepatitis (NASH), defined by hepatic fat deposition with hepatocellular damage, inflammation, and accumulating fibrosis. Several studies support an association between NAFLD and the incidence of cardiovascular diseases including atherosclerosis, a major cause of death worldwide. This pathological condition consists in a chronic and progressive inflammatory process in the intimal layer of large- and medium-sized arteries. The complications of advanced atherosclerosis include chronic or acute ischemic damage in the tissue perfused by the affected artery, leading to cellular death. By identifying specific targets influencing lipid metabolism and cardiovascular-related diseases, the present review highlights the role of MerTK in NAFLD-associated atherosclerotic lesions as a potential innovative therapeutic target. Therapeutic advantages might derive from the use of compounds selective for nuclear receptors targeting PPARs rather than LXRs regulating macrophage lipid metabolism and macrophage mediated inflammation, by favoring the expression of MerTK, which mediates an immunoregulatory action with a reduction in inflammation and in atherosclerosis.

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MERTK rs4374383 variant predicts incident nonalcoholic fatty liver disease and diabetes: role of mononuclear cell activation and adipokine response to dietary fat

Cited by 13 publications

References 0 publications

A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target

A Functional Role of GAS6/TAM in Nonalcoholic Steatohepatitis Progression Implicates AXL as Therapeutic Target

Serum Resistin Levels in Adult Patients with Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis

Role of Myeloid-Epithelial-Reproductive Tyrosine Kinase and Macrophage Polarization in the Progression of Atherosclerotic Lesions Associated With Nonalcoholic Fatty Liver Disease

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