Current and future pharmacological therapies for NAFLD/NASH

Sumida, Yoshio; Yoneda, Masashi

doi:10.1007/s00535-017-1415-1

Cited by 549 publications

(495 citation statements)

References 110 publications

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“…The MCD diet model is a well‐established experimental NAFLD model with features of hepatic steatosis which are similar to the pathological features of human NAFLD (Coulon et al, ). In addition, the value of anti‐inflammatory treatment for NAFLD has been demonstrated in several clinical trials (Sumida & Yoneda, ), and the MCD diet model is a typical inflammatory model, which is suitable for studying the role of potential drugs in preventing NAFLD, through inhibiting inflammation‐related pathways. The lack of VLDL secretion inhibited the transport of TG from liver into the circulation and resulted in severe hepatic TG accumulation and a reduced level of plasma TG in the MCD‐induced mouse model.…”

Section: Discussionmentioning

confidence: 99%

Naringenin attenuates non‐alcoholic fatty liver disease by down‐regulating the NLRP3/NF‐κB pathway in mice

Wang

et al. 2020

British J Pharmacology

174

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Background and Purpose Naringenin, a flavonoid compound with strong anti‐inflammatory activity, attenuated non‐alcoholic fatty liver disease (NAFLD) induced by a methionine‐choline deficient (MCD) diet in mice. However, the mechanisms underlying this suppression of inflammation and NAFLD remain unknown. Experimental Approach WT and NLRP3−/− mice were fed with MCD diet for 7 days to induce NAFLD and were given naringenin by gavage at the same time. in vitro experiments used HepG2 cells, primary hepatocytes, and Kupffer cells (KCs) stimulated by LPS or LPS plus oleic acid (OA). Key Results Treating WT mice with naringenin (100 mg·kg−1·day−1) attenuated hepatic lipid accumulation and inflammation in the livers of mice given the MCD diet. NLRP3−/− mice showed less hepatic lipid accumulation than WT mice, but naringenin did not ameliorate hepatic lipid accumulation further in NLRP3−/− mice. Treating the HepG2 cells with naringenin or NLRP3 inhibitor MCC950 reduced lipid accumulation. Naringenin inhibited activation of the NLRP3/NF‐κB pathway stimulated by OA together with LPS. In KCs isolated from WT mice, naringenin inhibited NLRP3 expression. Naringenin also inhibited lipid deposition, NLRP3 and IL‐1β expression in WT hepatocytes but was not effective in NLRP3−/− hepatocytes. After re‐expressing NLRP3 in NLRP3−/− hepatocytes by adenovirus, the anti‐lipid deposition effect of naringenin was restored. Conclusion and Implications Naringenin prevented NAFLD via down‐regulating the NLRP3/NF‐κB signalling pathway both in KCs and in hepatocytes, thus attenuating inflammation in the mice livers.

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Section: Discussionmentioning

confidence: 99%

Naringenin attenuates non‐alcoholic fatty liver disease by down‐regulating the NLRP3/NF‐κB pathway in mice

Wang

et al. 2020

British J Pharmacology

174

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“…Simtuzumab, a monoclonal antibody against lysyl oxidase homolog 2 (LOXL2), a collagen crosslinking enzyme, was ineffective in both IPF and NASH . ND‐L02‐s0201, which targets heat shock protein 47, a factor essential for maturation and secretion of collagen, is entering clinical trials …”

Section: A Complex Disease Distilled Into Four Processesmentioning

confidence: 99%

Disease pathways and molecular mechanisms of nonalcoholic steatohepatitis

Wegermann

Diehl

Moylan

2018

Clinical Liver Disease

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“…Early recognition of severe steatosis is thus imperative to prevent progression of disease. Histological grading of steatosis, together with inflammation, ballooning, and fibrosis, is a frequently used endpoint in clinical trials investigating novel therapies (11). Histological grading of steatosis, together with inflammation, ballooning, and fibrosis, is a frequently used endpoint in clinical trials investigating novel therapies (11).…”

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confidence: 99%

A Novel Automatic Digital Algorithm that Accurately Quantifies Steatosis in NAFLD on Histopathological Whole‐Slide Images

Munsterman

Erp

Weijers

et al. 2019

Cytometry Part B Clinical

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BackgroundAccurate assessment of hepatic steatosis is a key to grade disease severity in non‐alcoholic fatty liver disease (NAFLD).MethodsWe developed a digital automated quantification of steatosis on whole‐slide images (WSIs) of liver tissue and performed a validation study. Hematoxylin–eosin stained liver tissue slides were digitally scanned, and steatotic areas were manually annotated. We identified thresholds for size and roundness parameters by logistic regression to discriminate steatosis from surrounding liver tissue. The resulting algorithm produces a steatosis proportionate area (SPA; ratio of steatotic area to total tissue area described as percentage). The software can be implemented as a Java plug‐in in FIJI, in which digital WSI can be processed automatically using the Pathomation extension.ResultsWe obtained liver tissue specimens from 61 NAFLD patients and 18 controls. The area under the curve of correctly classified steatosis by the algorithm was 0.970 (95% CI 0.968–0.973), P < 0.001. Accuracy of the algorithm was 91.9%, with a classification error of 8.1%. SPA correlated significantly with steatosis grade (Rs = 0.845, CI: 0.749–0.902, P < 0.001) and increased significantly with each individual steatosis grade, except between Grade 2 and 3.ConclusionsWe have developed a novel digital analysis algorithm that accurately quantifies steatosis on WSIs of liver tissue. This algorithm can be incorporated when quantification of steatosis is warranted, such as in clinical trials studying efficacy of new therapeutic interventions in NAFLD. © 2019 The Authors. Cytometry Part B: Clinical Cytometry published by Wiley Periodicals, Inc. on behalf of International Clinical Cytometry Society.

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Current and future pharmacological therapies for NAFLD/NASH

Cited by 549 publications

References 110 publications

Naringenin attenuates non‐alcoholic fatty liver disease by down‐regulating the NLRP3/NF‐κB pathway in mice

Naringenin attenuates non‐alcoholic fatty liver disease by down‐regulating the NLRP3/NF‐κB pathway in mice

Disease pathways and molecular mechanisms of nonalcoholic steatohepatitis

A Novel Automatic Digital Algorithm that Accurately Quantifies Steatosis in NAFLD on Histopathological Whole‐Slide Images

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