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Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis.

ABSTRACT: Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show that holo- or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human genetic data. Furthermore, ADAM metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TGF?1 pathway that activates HSCs and induces liver fibrosis. These data provide insights into the role of liver macrophages in NASH fibrosis and provide a plausible mechanism underlying MERTK as a genetic risk factor for NASH fibrosis.

SUBMITTER: Cai B

PROVIDER: S-EPMC7004886 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis.

Cai Bishuang B Dongiovanni Paola P Corey Kathleen E KE Wang Xiaobo X Shmarakov Igor O IO Zheng Ze Z Kasikara Canan C Davra Viralkumar V Meroni Marica M Chung Raymond T RT Rothlin Carla V CV Schwabe Robert F RF Blaner William S WS Birge Raymond B RB Valenti Luca L Tabas Ira I

Cell metabolism 20191212 2

Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show ...[more]

PMID: 31839486

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Project description:This study aimed to investigate the beneficial effects of myricetin in a diet-induced nonalcoholic steatohepatitis (NASH) model and the underlying mechanism. C57BL/6J mice were fed a standard chow or the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 8 weeks with the treatment of myricetin (100 mg/kg) or vehicle by daily gavage. Hepatic inflammation, steatosis, fibrosis, and hepatic stellate cells (HSC) activation were assessed. We also analyzed M1 and M2 macrophages and its related markers in livers from NASH mice and in RAW264.7 macrophages stimulated by lipopolysaccharide (LPS) or interleukin 4 (IL-4) in vitro. Furthermore, we determined the effect of myricetin on the triggering receptor expressed on myeloid cells-1 (TREM-1), toll like receptor (TLR) 2 and 4, and myeloid differentiation factor 88 (MyD88) signaling both in livers from mice and in RAW264.7 cells stimulated by LPS. Our results revealed that myricetin remarkably ameliorated hepatic steatosis, inflammation, and inhibited hepatic macrophage infiltration in CDAHFD-fed mice. Myricetin-treated to CDAHFD-fed mice also inhibited liver fibrosis and HSC activation when compared with vehicle-treated to those mice. Moreover, myricetin inhibited M1 macrophage polarization and its relative markers in livers of NASH mice while induced M2 polarization. Similarly, in vitro study, myricetin inhibited the LPS-induced mRNA expression of M1 macrophages marker genes and induced IL-4-induced M2 macrophage marker genes in RAW264.7 macrophages. Mechanically, myricetin inhibited the expression of TREM-1 and TLR2/4-MyD88 signaling molecules in livers from NASH mice and in RAW264.7 macrophages stimulated by LPS in vitro. Additionally, myricetin inhibited the activation of nuclear factor (NF)-?B signaling and the phosphorylation of the signal transducer and activation of transcription 3 (STAT3) in LPS-stimulated RAW264.7 macrophages. Taken together, our data indicated that myricetin modulated the polarization of macrophages via inhibiting the TREM-1-TLR2/4-MyD88 signaling molecules in macrophages and therefore mitigated NASH and hepatic fibrosis in the CDAHFD-diet-induced NASH model in mice.

Project description:ImportanceNonalcoholic steatohepatitis (NASH) is projected to be the leading cause of liver transplantation by 2020. Advanced fibrosis (stage F3-F4) on liver biopsy independently predicts all-cause and liver-related mortality in NASH. There are no known efficacious treatments for advanced fibrosis related to NASH. Thiazolidinedione therapy has been extensively evaluated in NASH, and new randomized clinical trials (RCTs) of its efficacy have been completed.ObjectiveTo synthesize the evidence about the association of thiazolidinedione therapy with advanced liver fibrosis in NASH.Data sourcesMEDLINE, Ovid MEDLINE In-Process, Cochrane Library, EMBASE, clinicaltrials.gov, PubMed, and Scopus databases (without language restrictions), as well as other registries and scientific meeting presentations, from database inception through August 15, 2016.Study selectionRandomized clinical trials evaluating the effect of thiazolidinedione therapy on histologic features of the liver in biopsy-proven NASH.Data extraction and synthesisTwo investigators extracted study data independently and in duplicate and rated the risk of bias using the Cochrane Risk of Bias Tool.Main outcomes and measuresThe primary outcome was a dichotomous improvement in advanced fibrosis on liver biopsy, defined as an improvement in fibrosis stage from F3-F4 to F0-F2. Secondary outcomes were at least a 1-point improvement in fibrosis of any stage and NASH resolution. This meta-analysis also evaluated adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer, and anemia. With the use of random-effects models, dichotomous variables are presented as odds ratios (ORs) with 95% CIs, and continuous variables are presented as weighted mean differences with 95% CIs.ResultsThis study analyzed 8 RCTs (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25-7.93; P = .01; I2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12-2.47; P = .01; I2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001; I2 = 0%). Analyses restricted to RCTs enrolling patients without diabetes yielded similar results for improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04-10.90; P = .02; I2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02-3.03; P = .02; I2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95-5.93; P < .001; I2 = 0%). All effects were accounted for by pioglitazone use. Weight gain and lower limb edema occurred more frequently with thiazolidinedione therapy (initial body weight +2.70%; 95% CI, 1.96%-4.34%; P = .001). The small sample size of included RCTs prevented evaluation of more serious adverse effects of thiazolidinedione therapy.Conclusions and relevancePioglitazone use improves advanced fibrosis in NASH, even in patients without diabetes. Whether this finding translates to improvement in risk for clinical outcomes requires further study.

Project description:Background and aimsThe augmenter of liver regeneration (ALR) protein is critical for lipid homeostasis and mitochondrial function. We investigated high-fat/high-carbohydrate (HF/HC) diet-induced nonalcoholic fatty liver disease (NAFLD) in wild-type (WT), hepatocyte-specific ALR-knockout (ALR-H-KO), and ALR-heterozygous (ALR-H-HET) mice. ALR was measured in serum of human nonalcoholic steatohepatitis (NASH) and NASH-induced cirrhosis (serum and liver).Approach and resultsHF/HC feeding decreased ALR expression in all groups of mice. The otherwise normal ALR-H-HET mice gained more weight and steatosis than WT mice when challenged metabolically with the HF/HC diet; ALR-H-KO mice gained the least weight and had the least steatosis. These findings were consistent with correspondingly increased triglycerides and cholesterol and altered expression of carnitine palmitoyltransferase 1a, sterol regulatory element-binding protein, acetyl coenzyme A carboxylase, and fatty acid synthase. All HF/HC-fed mice developed insulin resistance, the magnitude being lower in ALR-H-KO mice. HF/HC-fed ALR-H-HET mice were more resistant to glucose challenge than WT or ALR-H-KO mice. The frequency of tumor necrosis factor alpha-producing, interleukin 6 (IL6)-producing, and IL17-producing cells was greater in ALR-H-KO than ALR-H-HET and lowest in WT mice. HF/HC feeding did not increase their number in ALR-H-KO mice, and the increase in ALR-H-HET was greater than that in WT mice except for IL17 cells. Cluster of differentiation 25-positive (CD25+ ) forkhead box P3-positive CD4+ regulatory T-cell frequency was lower in ALR-H-HET than WT mice and further reduced in ALR-H-KO mice; HF/HC reduced regulatory T-cell frequency only in WT mice. HF/HC-fed ALR-H-HET, but not WT, mice developed fibrosis; and ALR-H-KO mice progressed to cirrhosis. White adipose tissue of HF/HC-fed ALR-deficient mice developed strong inflammation, indicating bidirectional interactions with the liver. Hepatic and serum ALR levels were significantly reduced in patients with NASH-cirrhosis. Serum ALR was also significantly lower in patients with NASH.ConclusionsHepatic ALR deficiency may be a critical predisposing factor for aggressive NAFLD progression.

Dataset Information

Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis.

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Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis.

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