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For: Day CP. Non-alcoholic steatohepatitis (NASH): where are we now and where are we going? Gut 2002;50:585-8. [PMID: 11950797 PMCID: PMC1773193 DOI: 10.1136/gut.50.5.585] [Citation(s) in RCA: 135] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]

For:	Day CP. Non-alcoholic steatohepatitis (NASH): where are we now and where are we going? Gut 2002;50:585-8. [PMID: 11950797 PMCID: PMC1773193 DOI: 10.1136/gut.50.5.585] [Citation(s) in RCA: 135] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [What about the content of this article? (0)] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]

Number

Cited by Other Article(s)

Savari F, Mard SA. Nonalcoholic steatohepatitis: A comprehensive updated review of risk factors, symptoms, and treatment. Heliyon 2024;10:e28468. [PMID: 38689985 PMCID: PMC11059522 DOI: 10.1016/j.heliyon.2024.e28468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 03/17/2024] [Accepted: 03/19/2024] [Indexed: 05/02/2024] Open

Zhu Y, Tang H, Zhao H, Lu J, Lin K, Ni J, Zhao B, Wu G, Tan C. Vinpocetine represses the progression of nonalcoholic steatohepatitis in mice by mediating inflammasome components via NF-κB signaling. GASTROENTEROLOGIA Y HEPATOLOGIA 2024;47:366-376. [PMID: 37562770 DOI: 10.1016/j.gastrohep.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 06/15/2023] [Accepted: 07/18/2023] [Indexed: 08/12/2023]

Hu Y, Peng X, Du G, Zhai Y, Xiong X, Luo X. Dihydroartemisinin ameliorates the liver steatosis in metabolic associated fatty liver disease mice by attenuating the inflammation and oxidative stress and promoting autophagy. Acta Cir Bras 2023;38:e385023. [PMID: 37851788 PMCID: PMC10578105 DOI: 10.1590/acb385023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 03/04/2023] [Indexed: 10/20/2023] Open

Onwuzo SS, Hitawala AA, Boustany A, Kumar P, Almomani A, Onwuzo C, Monteiro JM, Asaad I. Prevalence of non-alcoholic fatty liver disease in patients with nephrotic syndrome: A population-based study. World J Hepatol 2023;15:265-273. [PMID: 36926242 PMCID: PMC10011912 DOI: 10.4254/wjh.v15.i2.265] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/21/2023] [Accepted: 02/08/2023] [Indexed: 02/24/2023] Open

Abstract

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is a global health concern with a prevalence of about 25% amongst United States adults. Its increased prevalence is attributed to increase in patients with obesity and metabolic syndrome, partly due to similar mechanisms of injury. Nephrotic syndrome (NS) is a clinical entity resulting from extensive proteinuria leading to hypoalbuminemia, hyperlipidemia, edema, and other complications. Given its association with hyperlipidemia, there is concern that patients with NS may be at increased risk of NAFLD.

AIM

To perform a cross-sectional population-based study to investigate the prevalence and risk factors of NAFLD in patients with NS.

METHODS

A large multicenter database (Explorys Inc., Cleveland, OH, United States) was utilized for this retrospective cohort study. A cohort of 49700 patients with a diagnosis of “Non-Alcoholic fatty liver disease” using the Systematized Nomenclature of Medicine-Clinical Terms (SNOMED-CT) between 1999-2022 was identified. Inclusion criteria were age ≥ 18 years, presence of NAFLD, presence of NS. There were no specific exclusion criteria. Univariate and multivariate analysis were performed to adjust for multiple risk factors including age, gender, Caucasian race, NS, type II diabetes mellitus, hypothyroidism, dyslipidemia, obesity, metabolic syndrome and chronic kidney disease. Statistical analysis was conducted using R, and for all analyses, a 2-sided P value of < 0.05 was considered statistically significant.

RESULTS

Among the 78734750 individuals screened in this database, there were a total of 49700 subjects with NAFLD. In univariate analysis, the odds of having NAFLD in patients with NS, type 2 diabetes mellitus, hypothyroidism, dyslipidemia, obesity, metabolic syndrome and chronic kidney disease were 14.84 [95% confidence interval (95%CI) 13.67-16.10], 17.05 (95%CI 16.78-17.32), 6.99 (95%CI 6.87-7.11), 13.61 (95%CI 13.38-13.84), 19.19 (95%CI 18.89-19.50), 29.09 (95%CI 28.26--29.95), and 9.05 (95%CI 8.88-9.22), respectively. In multivariate analysis, the odds of having NAFLD amongst patients with NS were increased to 1.85 (95%Cl 1.70-2.02), while the odds were also remained high in patients that have type 2 diabetes mellitus [odds ratio (OR) 3.84], hypothyroidism (OR 1.57), obesity (OR 5.10), hyperlipidemia (OR 3.09), metabolic syndrome (OR 3.42) and chronic kidney disease (OR 1.33).

CONCLUSION

Patients with NS are frequently found to have NAFLD, even when adjusting for common risk factors. Hence, clinicians should maintain a high index of suspicion regarding presence of NAFLD in patients with NS.

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Mitochondrial Peroxiredoxin III Protects against Non-Alcoholic Fatty Liver Disease Caused by a Methionine-Choline Deficient Diet. Antioxidants (Basel) 2022;12:antiox12010009. [PMID: 36670871 PMCID: PMC9855157 DOI: 10.3390/antiox12010009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/09/2022] [Accepted: 12/17/2022] [Indexed: 12/24/2022] Open

Zhang X, Gao R, Zhou Z, Sun J, Tang X, Li J, Zhou X, Shen T. Uncovering the mechanism of Huanglian-Wuzhuyu herb pair in treating nonalcoholic steatohepatitis based on network pharmacology and experimental validation. JOURNAL OF ETHNOPHARMACOLOGY 2022;296:115405. [PMID: 35644437 DOI: 10.1016/j.jep.2022.115405] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/21/2022] [Accepted: 05/23/2022] [Indexed: 05/05/2023]

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE

The Huanglian-Wuzhuyu herb pair (HWHP) is a classic Chinese herbal formula consisting of the root of Coptis chinensis Franch and dried, nearly mature scented fruit of Tetradium ruticarpum (A.Juss.) T.G.Hartley. It is widely utilized to treat gastrointestinal and liver diseases such as diarrhea, dysentery, cholestasis, hepatocellular carcinoma, and nonalcoholic steatohepatitis (NASH). However, the mechanism of HWHP in treating NASH remains poorly understood.

AIM OF THE STUDY

This study investigated the mechanisms of HWHP in NASH treatment via network pharmacology and validated the results through in vivo experiment using mouse models.

MATERIALS AND METHODS

The compounds and targets corresponding to the active ingredients of HWHP were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The genes associated with NASH were obtained from the DisGeNET database. Cytoscape software was employed to construct a "drug-ingredient-target-disease" network. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were employed to analyze the related signaling pathways affected by HWHP. Moreover, AutoDock software was used to assess the potential binding affinity between the key targets of the hub pathway and the bioactive compounds. Subsequently, in vivo experiment was conducted to verify the findings of network pharmacology.

RESULTS

A total of 41 active compounds and 198 targets of HWHP were screened, of which 51 common targets were related to NASH. GO functional enrichment analysis revealed that HWHP may affect NASH by modulating inflammatory response. KEGG pathway enrichment suggested that the NOD-like receptor (NLR) signaling pathway may play an important role in treating NASH. Molecular docking results demonstrated that most HWHP components were successfully docked to NLRP3 with good binding energy. In vivo experiments revealed that HWHP alleviated liver inflammation, improved liver steatosis, reduced TC, TG, LDL-C, ALT, and AST, decreased mRNA expressions of IL-6, IL-18, and TNF-α in the liver, and lowered the expressions of NLRP3, pro-IL-1β, and ASC protein. Also, immunohistochemical findings presented downregulation of caspase-1 and IL-1β by HWHP.

CONCLUSIONS

The results disclosed that HWHP ameliorates NASH in mice by reducing inflammation and liver steatosis via inhibition of NLRP3 inflammasome. This study revealed the mechanism of HWHP in treating NASH through experiments.

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Gao R, Zhang X, Zhou Z, Sun J, Tang X, Li J, Zhou X, Shen T. Pharmacological Mechanism of Ganlu Powder in the Treatment of NASH Based on Network Pharmacology and Molecular Docking. DISEASE MARKERS 2022;2022:7251450. [PMID: 35811658 PMCID: PMC9259220 DOI: 10.1155/2022/7251450] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 11/30/2022]

A Decade of Mighty Lipophagy: What We Know and What Facts We Need to Know? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021;2021:5539161. [PMID: 34777688 PMCID: PMC8589519 DOI: 10.1155/2021/5539161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 09/30/2021] [Accepted: 10/15/2021] [Indexed: 12/24/2022]

Coni P, Pichiri G, Lachowicz JI, Ravarino A, Ledda F, Fanni D, Gerosa C, Piras M, Coghe F, Gibo Y, Cau F, Castagnola M, Van Eyken P, Saba L, Piludu M, Faa G. Zinc as a Drug for Wilson's Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury. Molecules 2021;26:6614. [PMID: 34771023 PMCID: PMC8587580 DOI: 10.3390/molecules26216614] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 10/29/2021] [Indexed: 02/07/2023] Open

Affiliation(s)

Pierpaolo Coni Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Giuseppina Pichiri Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Joanna Izabela Lachowicz Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Alberto Ravarino Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Francesca Ledda Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Daniela Fanni Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Clara Gerosa Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Monica Piras Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Ferdinando Coghe Dipartimento Servizi di Diagnosi e Cura, Azienda Ospedaliero-Universitaria di Cagliari (A.O.U.), University of Cagliari, 09024 Cagliari, Italy;
Yukio Gibo Hepatology Clinic, 1-34-20 Muraimachiminami, Matsumoto, Nagano 399-0036, Japan;
Flaviana Cau Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.)
Massimo Castagnola Laboratorio di Proteomica e Metabonomica-Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia, 00013 Rome, Italy;
Peter Van Eyken Department of Pathology, Genk Regional Ziekenhuis, 3600 Genk, Belgium;
Luca Saba Department of Radiology, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari—Polo di Monserrato s.s. 554, 09045 Monserrato, Italy;
Marco Piludu Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy;
Gavino Faa Department of Medical Sciences and Public Health, University of Cagliari, 09042 Monserrato, Italy; (P.C.); (A.R.); (F.L.); (D.F.); (C.G.); (M.P.); (F.C.); (G.F.) UOC Anatomia Patologica, AOU Cagliari, University of Cagliari, 09124 Cagliari, Italy

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Kim MC, Lee JI, Kim JH, Kim HJ, Cho YK, Jeon WK, Kim BI, Sohn W. Serum zinc level and hepatic fibrosis in patients with nonalcoholic fatty liver disease. PLoS One 2020;15:e0240195. [PMID: 33095789 PMCID: PMC7584204 DOI: 10.1371/journal.pone.0240195] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 09/22/2020] [Indexed: 12/16/2022] Open

Wei R, Han C, Deng D, Ye F, Gan X, Liu H, Li L, Xu H, Wei S. Research progress into the physiological changes in metabolic pathways in waterfowl with hepatic steatosis. Br Poult Sci 2020;62:118-124. [DOI: 10.1080/00071668.2020.1812527] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]

Shao C, Ye J, Li F, Lin Y, Wu T, Wang W, Feng S, Zhong B. Early Predictors of Cardiovascular Disease Risk in Nonalcoholic Fatty Liver Disease: Non-obese Versus Obese Patients. Dig Dis Sci 2020;65:1850-1860. [PMID: 31724099 DOI: 10.1007/s10620-019-05926-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 10/30/2019] [Indexed: 02/08/2023]

Abstract

BACKGROUND

Nonalcoholic fatty liver disease (NAFLD) is regarded as a risk factor of cardiovascular disease (CVD). However, the association between non-obese NAFLD and CVD has not been well established.

AIM

We aimed to compare the CVD risk between non-obese and obese NAFLD patients, and explored the factors associated with subclinical atherosclerosis.

METHOD

Consecutive NAFLD patients estimated by magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) were recruited. Liver fat content (LFC) and liver stiffness were measured with MRI-PDFF and shear wave elastography, respectively. CVD risk was estimated by atherosclerosis index (AI), carotid intima-media thickness, carotid plaque, and Framingham risk score (FRS).

RESULTS

This study included 543 NAFLD patients. The presence of carotid intima-media thickening and carotid plaque, FRS, and AI were comparable between non-obese and obese patients. Age increased per 10 years (OR 9.68; P < 0.001) and liver fibrosis (liver stiffness > 6.1 kPa, OR 4.42; P = 0.004) were significant factors associated with carotid intima-media thickening in non-obese patients, while age increased per 10 years (OR 2.02; P < 0.001), liver fibrosis (OR 2.18; P = 0.039), and LFC > 10% (OR 2.29; P = 0.021) were independent predictors in obese patients. Only elevated triglyceride was significantly associated with carotid plaque in non-obese patients (OR 2.42; P = 0.033), while age increased per 10 years (OR 1.77; P = 0.002) and LFC > 10% (OR 2.83; P = 0.019) were significant predictors in obese patients.

CONCLUSIONS

Liver stiffness and age were strongly predictive of subclinical atherosclerosis in all NAFLD, while LFC was an additional predictor in obese NAFLD patients. Our findings highlight that early CVD screening strategy should be established for NAFLD patients according to different BMIs.

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Reddy YK, Marella HK, Jiang Y, Ganguli S, Snell P, Podila PS, Maliakkal B, Satapathy SK. Natural History of Non-Alcoholic Fatty Liver Disease: A Study With Paired Liver Biopsies. J Clin Exp Hepatol 2020;10:245-254. [PMID: 32405181 PMCID: PMC7212293 DOI: 10.1016/j.jceh.2019.07.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/05/2019] [Indexed: 02/06/2023] Open

Aisa Y, Yunusi K, Chen Q, Mi N. Systematic understanding of the potential targets and pharmacological mechanisms of acteoside by network pharmacology approach. Med Chem Res 2020. [DOI: 10.1007/s00044-020-02524-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]

Faheem SA, Saeed NM, El-Naga RN, Ayoub IM, Azab SS. Hepatoprotective Effect of Cranberry Nutraceutical Extract in Non-alcoholic Fatty Liver Model in Rats: Impact on Insulin Resistance and Nrf-2 Expression. Front Pharmacol 2020;11:218. [PMID: 32256346 PMCID: PMC7093716 DOI: 10.3389/fphar.2020.00218] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Accepted: 02/14/2020] [Indexed: 12/15/2022] Open

Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) is a pathological accumulation of triglycerides (TGs) in the hepatocyte in the absence of alcohol intake. Untreated NAFLD is expected to progress into liver fibrosis. Cranberry is rich in polyphenols with antioxidant and anti-inflammatory activities.

Hypothesis

The present study was performed to evaluate our hypothesis of the possible anti-fibrotic effect of cranberry nutraceuticals in a high fat cholesterol diet induced (HFCD)-NAFLD in rats, focusing on improving insulin sensitivity and modulating the expression of nuclear factor erythroid-2-related factor-2 (Nrf2) (a transcription factor responsible for regulating cellular redox balance).

Method

Male albino wistar rats (12 weeks) received HFCD and/or cranberry (50 and 100 mg/kg/day, three times/week) orally for 8 consecutive weeks.

Results

In comparison to the HFCD group, cranberry treated groups (50 and 100 mg/kg) showed marked hepatoprotection, where it significantly decreased liver enzymes (alanine transaminases by 49 and 64% and aspartate transaminases by 45 and 64%; respectively), TGs, and ameliorated the histopathological alterations (such as inflammatory cells infiltration and ballooning degeneration) induced by HFCD. Cranberry also alleviated oxidative stress (malondialdehyde, glutathione, catalase and superoxide dismutase) and inflammation (tumor necrosis factor- alpha, interleukine-6 and nuclear factor kappa-b) and significantly reduced the HOMA-IR and TyG index. On the other hand, cranberry treated groups (50 and 100 mg/kg) showed a marked increase in the expression of adiponectin, by 8 and 13-fold, insulin receptor substrate-2 by 21 and 79%, and Nrf2 by 13 and 61%, respectively. Notably, cranberry significantly reduced the fibrotic markers, TGF–β and α-SMA expression and collagen deposition.

Conclusion

The present study showed that cranberry significantly attenuated NAFLD, in a dose dependent manner, which could be partially recognized by its antioxidant, anti-inflammatory activities, and its ability to improve insulin sensitivity. Notably, our study proves for the first time that the anti-fibrotic activity of cranberry is promising.

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Honda Y, Imajo K, Kobayashi T, Kessoku T, Ogawa Y, Tomeno W, Yoneda M, Kobayashi N, Saito S, Nakajima A. Autotaxin is a valuable biomarker for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. Hepatol Res 2019;49:1136-1146. [PMID: 31144415 DOI: 10.1111/hepr.13382] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 05/15/2019] [Accepted: 05/20/2019] [Indexed: 12/12/2022]

Park JS, Lee DH, Lee YS, Oh E, Bae KH, Oh KJ, Kim H, Bae SH. Dual roles of ULK1 (unc-51 like autophagy activating kinase 1) in cytoprotection against lipotoxicity. Autophagy 2019;16:86-105. [PMID: 30907226 DOI: 10.1080/15548627.2019.1598751] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open

Abstract

Saturated fatty acid (SFA)-induced lipotoxicity is caused by the accumulation of reactive oxygen species (ROS), which is associated with damaged mitochondria. Moreover, lipotoxicity is crucial for the progression of nonalcoholic steatohepatitis (NASH). Autophagy is required for the clearance of protein aggregates or damaged mitochondria to maintain cellular metabolic homeostasis. The NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2)-KEAP1 (kelch like ECH associated protein 1) pathway is essential for the elimination of ROS. ULK1 (unc-51 like autophagy activating kinase 1; yeast Atg1) is involved in the initiation of autophagy; however, its role in lipotoxicity-induced cell death in hepatocytes and mouse liver has not been elucidated. We now show that ULK1 potentiates the interaction between KEAP1 and the autophagy adaptor protein SQSTM1/p62, thereby mediating NFE2L2 activation in a manner requiring SQSTM1-dependent autophagic KEAP1 degradation. Furthermore, ULK1 is required for the autophagic removal of damaged mitochondria and to enhance binding between SQSTM1 and PINK1 (PTEN induced kinase 1). This study demonstrates the molecular mechanisms underlying the cytoprotective role of ULK1 against lipotoxicity. Thus, ULK1 could represent a potential therapeutic target for the treatment of NASH.Abbreviations: ACTB: actin beta; CM-H₂DCFDA:5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate; CQ: chloroquine; CUL3: cullin 3; DMSO: dimethyl sulfoxide; GSTA1: glutathione S-transferase A1; HA: hemagglutinin; Hepa1c1c7: mouse hepatoma cells; HMOX1/HO-1: heme oxygenase 1; KEAP1: kelch like ECH associated protein 1; LPS: lipopolysaccharides; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK8/JNK: mitogen-activated protein kinase 8; MEF: mouse embryonic fibroblast; MFN1: mitofusin 1; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NASH: nonalcoholic steatohepatitis; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PA: palmitic acid; PARP: poly (ADP-ribose) polymerase 1; PINK1: PTEN induced kinase 1; PRKAA1/2: protein kinase AMP-activated catalytic subunits alpha1/2; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; PRKC/PKC: protein kinase C; RBX1: ring-box 1; ROS: reactive oxygen species; SFA: saturated fatty acid; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUBA: tubulin alpha; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling; ULK1: unc-51 like autophagy activating kinase 1.

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Melatonin prevents chronic intermittent hypoxia-induced injury by inducing sirtuin 1-mediated autophagy in steatotic liver of mice. Sleep Breath 2018;23:825-836. [PMID: 30411173 PMCID: PMC6700047 DOI: 10.1007/s11325-018-1741-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Revised: 09/27/2018] [Accepted: 10/08/2018] [Indexed: 12/31/2022]

Abstract

BACKGROUND

Hepatic steatosis that occasionally results in nonalcoholic steatohepatitis (NASH) is related to obstructive sleep apnea (OSA). Many studies have shown that autophagy exerts protective effects on liver damage caused by various diseases and melatonin exhibits hepatoprotective properties. However, the mechanisms of liver injury induced by chronic intermittent hypoxia (CIH) and the effect of melatonin on the regulation of liver injury remain unclear.

PURPOSE

This study was aimed to evaluate the role of CIH in steatohepatitis progression and the regulatory function of melatonin on fatty liver sensitivity to CIH injury, mainly focusing on autophagy signaling.

METHODS

A high-fat diet (FD)-induced obesity mouse model was subjected to intermittent hypoxia/normoxia events for approximately 8 h per day using an autophagy agonist, rapamycin, or an inhibitor, 3-methyladenine (3-MA), and SRT1720, a sirtuin 1 (SIRT1) activator, or sirtinol, a SIRT1 inhibitor, with or without melatonin for a total of six successive weeks, followed by assessment of expression of autophagy-related genes and activity of serum aminotransferase as well as histological evaluation of tissue morphology.

RESULTS

Neither FD nor CIH alone causes significant liver injury; however, the combination yielded higher serum aminotransferase activities and more severe histological changes, accompanied by a decrease in autophagy activity. Melatonin markedly inhibited FD/CIH-stimulated liver injury by enhancing autophagy. In contrast, SIRT1 inhibition resulted in a decrease in the expression of melatonin-induced autophagy-related genes as well as diminished its protective effects on FD/CIH-induced liver injury.

CONCLUSION

These results suggest that melatonin could ameliorate FD/CIH-induced hepatocellular damage by activating SIRT1-mediated autophagy signaling.

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Takaki Y, Mizuochi T, Nishioka J, Eda K, Yatsuga S, Yamashita Y. Nonalcoholic fatty liver disease with prolactin-secreting pituitary adenoma in an adolescent: A case report. Medicine (Baltimore) 2018;97:e12879. [PMID: 30335007 PMCID: PMC6211884 DOI: 10.1097/md.0000000000012879] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 09/25/2018] [Indexed: 01/01/2023] Open

Yoneda M, Imajo K, Takahashi H, Ogawa Y, Eguchi Y, Sumida Y, Yoneda M, Kawanaka M, Saito S, Tokushige K, Nakajima A. Clinical strategy of diagnosing and following patients with nonalcoholic fatty liver disease based on invasive and noninvasive methods. J Gastroenterol 2018;53:181-196. [PMID: 29177681 PMCID: PMC5846871 DOI: 10.1007/s00535-017-1414-2] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 11/13/2017] [Indexed: 02/04/2023]

Li J, Guo QJ, Cai JZ, Pan C, Shen ZY, Jiang WT. Simultaneous liver, pancreas-duodenum and kidney transplantation in a patient with hepatitis B cirrhosis, uremia and insulin dependent diabetes mellitus. World J Gastroenterol 2017;23:8104-8108. [PMID: 29259387 PMCID: PMC5725306 DOI: 10.3748/wjg.v23.i45.8104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 08/27/2017] [Accepted: 09/13/2017] [Indexed: 02/06/2023] Open

Gellrich L, Merk D. Therapeutic Potential of Peroxisome Proliferator-Activated Receptor Modulation in Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis. NUCLEAR RECEPTOR RESEARCH 2017. [DOI: 10.11131/2017/101310] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open

Puoti C, Elmo MG, Ceccarelli D, Ditrinco M. Liver steatosis: The new epidemic of the Third Millennium. Benign liver state or silent killer? Eur J Intern Med 2017;46:1-5. [PMID: 28688543 DOI: 10.1016/j.ejim.2017.06.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 06/29/2017] [Indexed: 12/15/2022]

Honda Y, Kessoku T, Sumida Y, Kobayashi T, Kato T, Ogawa Y, Tomeno W, Imajo K, Fujita K, Yoneda M, Kataoka K, Taguri M, Yamanaka T, Seko Y, Tanaka S, Saito S, Ono M, Oeda S, Eguchi Y, Aoi W, Sato K, Itoh Y, Nakajima A. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. BMC Gastroenterol 2017;17:96. [PMID: 28789631 PMCID: PMC5549431 DOI: 10.1186/s12876-017-0652-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 07/31/2017] [Indexed: 12/14/2022] Open

Affiliation(s)

Yasushi Honda Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Takaomi Kessoku Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Yoshio Sumida Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Aichi, Japan
Takashi Kobayashi Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Takayuki Kato Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Yuji Ogawa Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Wataru Tomeno Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Kento Imajo Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Koji Fujita Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Masato Yoneda Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Koshi Kataoka Department of Biostatistics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Masataka Taguri Department of Biostatistics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Takeharu Yamanaka Department of Biostatistics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Yuya Seko Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Saiyu Tanaka Center for Digestive and Liver Diseases, Nara City Hospital, Nara, Japan
Satoru Saito Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Masafumi Ono Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
Satoshi Oeda Liver Center, Saga University Hospital, Saga, Japan
Yuichiro Eguchi Liver Center, Saga University Hospital, Saga, Japan
Wataru Aoi Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
Kenji Sato Division of Applied Biosciences, Graduate School of Agriculture, Kyoto University, Kyoto, Japan
Yoshito Itoh Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Atsushi Nakajima Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

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Okajima A, Sumida Y, Taketani H, Hara T, Seko Y, Ishiba H, Nishimura T, Umemura A, Nishikawa T, Yamaguchi K, Moriguchi M, Mitsuyoshi H, Yasui K, Minami M, Itoh Y. Liver stiffness measurement to platelet ratio index predicts the stage of liver fibrosis in non-alcoholic fatty liver disease. Hepatol Res 2017;47:721-730. [PMID: 27539017 DOI: 10.1111/hepr.12793] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/08/2016] [Accepted: 08/10/2016] [Indexed: 12/18/2022]

Reexamining the Association of Body Mass Index With Overall Survival Outcomes After Liver Transplantation. Transplant Direct 2017;3:e172. [PMID: 28706975 PMCID: PMC5498013 DOI: 10.1097/txd.0000000000000681] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 04/07/2017] [Indexed: 01/05/2023] Open

Drescher HK, Schippers A, Clahsen T, Sahin H, Noels H, Hornef M, Wagner N, Trautwein C, Streetz KL, Kroy DC. β₇-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis. J Hepatol 2017;66:1251-1264. [PMID: 28192190 DOI: 10.1016/j.jhep.2017.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Revised: 12/30/2016] [Accepted: 02/01/2017] [Indexed: 02/08/2023]

Abstract

BACKGROUND & AIMS

Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. It is unclear how infiltrating leukocytes affect NASH-development. Our study aims to investigate the role of the homing/receptor, pair mucosal addressin cell adhesion molecule-1 (MAdCAM-1)/β₇-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model.

METHODS

Constitutive β₇-Integrin deficient (β₇^-/-) and MAdCAM-1 deficient (MAdCAM-1^-/-) mice were fed a high fat diet (HFD) for 26weeks or methionine-choline-deficient-diet (MCD) for 4weeks.

RESULTS

β₇^-/- mice displayed earlier and more progressive steatohepatitis during HFD- and MCD-treatment, while MAdCAM-1^-/- mice showed less histomorphological changes. The anti-oxidative stress response was significantly weaker in β₇^-/- mice as reflected by a significant downregulation of the transcription factors nuclear-factor(erythroid-derived 2)-like 2 (Nrf2) and heme-oxigenase-1 (HO-1). Additionally, stronger dihydroethidium-staining revealed an increased oxidative stress response in β₇^-/- animals. In contrast, MAdCAM-1^-/- mice showed an upregulation of the anti-oxidative stress response. β₇^-/- animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (T_Reg) markers as well as numbers of anti-inflammatory macrophages was significantly enhanced in MAdCAM-1^-/- mice. Those changes finally resulted in earlier and stronger collagen accumulation in β₇^-/- mice, whereas MAdCAM-1^-/- mice were protected from fibrosis initiation.

CONCLUSIONS

Adhesion molecule mediated effector cell migration contributes to the outcome of steatohepatitis in the HFD- and the MCD model. While MAdCAM-1 promotes steatohepatitis, β₇-Integrin unexpectedly exerts protective effects. β₇^-/- mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of β₇-Integrins and their receptor MAdCAM-1 provide novel targets for therapeutic interventions in steatohepatitis.

LAY SUMMARY

The mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is expressed in livers upon diet-induced non-alcoholic steatohepatitis (NASH). Loss of MAdCAM-1 has beneficial effects regarding the development of NASH - manifested by reduced hepatic oxidative stress and decreased inflammation. In contrast, β₇-Integrin-deficiency results in increased steatohepatitis.

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Spahis S, Delvin E, Borys JM, Levy E. Oxidative Stress as a Critical Factor in Nonalcoholic Fatty Liver Disease Pathogenesis. Antioxid Redox Signal 2017;26:519-541. [PMID: 27452109 DOI: 10.1089/ars.2016.6776] [Citation(s) in RCA: 286] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]

Jeong HS, Kim KH, Lee IS, Park JY, Kim Y, Kim KS, Jang HJ. Ginkgolide A ameliorates non-alcoholic fatty liver diseases on high fat diet mice. Biomed Pharmacother 2017;88:625-634. [PMID: 28142119 DOI: 10.1016/j.biopha.2017.01.114] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 01/17/2017] [Accepted: 01/18/2017] [Indexed: 12/14/2022] Open

Park SB, Park JS, Jung WH, Kim HY, Kwak HJ, Ahn JH, Choi KJ, Na YJ, Choi S, Dal Rhee S, Kim KY. Anti-inflammatory effect of a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages. J Pharmacol Sci 2016;131:241-50. [DOI: 10.1016/j.jphs.2016.07.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 07/03/2016] [Accepted: 07/05/2016] [Indexed: 11/25/2022] Open

Vecchione G, Grasselli E, Voci A, Baldini F, Grattagliano I, Wang DQH, Portincasa P, Vergani L. Silybin counteracts lipid excess and oxidative stress in cultured steatotic hepatic cells. World J Gastroenterol 2016;22:6016-6026. [PMID: 27468193 PMCID: PMC4948277 DOI: 10.3748/wjg.v22.i26.6016] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 05/19/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open

Abstract

AIM

To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis.

METHODS

Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 μmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays.

RESULTS

Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-κB). Incubation of steatotic cells with silybin 50 μmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation.

CONCLUSION

We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.

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Chon YE, Kim KJ, Jung KS, Kim SU, Park JY, Kim DY, Ahn SH, Chon CY, Chung JB, Park KH, Bae JC, Han KH. The Relationship between Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease Measured by Controlled Attenuation Parameter. Yonsei Med J 2016;57:885-892. [PMID: 27189281 PMCID: PMC4951464 DOI: 10.3349/ymj.2016.57.4.885] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 09/21/2015] [Accepted: 10/17/2015] [Indexed: 01/02/2023] Open

Affiliation(s)

Young Eun Chon Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
Kwang Joon Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Executive Healthcare Clinic, Severance Hospital, Yonsei Health System, Seoul, Korea
Kyu Sik Jung Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
Seung Up Kim Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
Jun Yong Park Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
Do Young Kim Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
Sang Hoon Ahn Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
Chae Yoon Chon Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea
Jae Bock Chung Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea Executive Healthcare Clinic, Severance Hospital, Yonsei Health System, Seoul, Korea
Kyeong Hye Park Executive Healthcare Clinic, Severance Hospital, Yonsei Health System, Seoul, Korea
Ji Cheol Bae Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Kwang Hyub Han Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Liver Cirrhosis Clinical Research Center, Seoul, Korea.

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Alam S, Mustafa G, Alam M, Ahmad N. Insulin resistance in development and progression of nonalcoholic fatty liver disease. World J Gastrointest Pathophysiol 2016;7:211-217. [PMID: 27190693 PMCID: PMC4867400 DOI: 10.4291/wjgp.v7.i2.211] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 01/03/2016] [Accepted: 03/07/2016] [Indexed: 02/06/2023] Open

Imajo K, Kessoku T, Honda Y, Tomeno W, Ogawa Y, Mawatari H, Fujita K, Yoneda M, Taguri M, Hyogo H, Sumida Y, Ono M, Eguchi Y, Inoue T, Yamanaka T, Wada K, Saito S, Nakajima A. Magnetic Resonance Imaging More Accurately Classifies Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease Than Transient Elastography. Gastroenterology 2016;150:626-637.e7. [PMID: 26677985 DOI: 10.1053/j.gastro.2015.11.048] [Citation(s) in RCA: 584] [Impact Index Per Article: 64.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Revised: 11/20/2015] [Accepted: 11/21/2015] [Indexed: 02/06/2023]

Abstract

BACKGROUND & AIMS

Noninvasive methods have been evaluated for the assessment of liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD). We compared the ability of transient elastography (TE) with the M-probe, and magnetic resonance elastography (MRE) to assess liver fibrosis. Findings from magnetic resonance imaging (MRI)-based proton density fat fraction (PDFF) measurements were compared with those from TE-based controlled attenuation parameter (CAP) measurements to assess steatosis.

METHODS

We performed a cross-sectional study of 142 patients with NAFLD (identified by liver biopsy; mean body mass index, 28.1 kg/m(2)) in Japan from July 2013 through April 2015. Our study also included 10 comparable subjects without NAFLD (controls). All study subjects were evaluated by TE (including CAP measurements), MRI using the MRE and PDFF techniques.

RESULTS

TE identified patients with fibrosis stage ≥2 with an area under the receiver operating characteristic (AUROC) curve value of 0.82 (95% confidence interval [CI]: 0.74-0.89), whereas MRE identified these patients with an AUROC curve value of 0.91 (95% CI: 0.86-0.96; P = .001). TE-based CAP measurements identified patients with hepatic steatosis grade ≥2 with an AUROC curve value of 0.73 (95% CI: 0.64-0.81) and PDFF methods identified them with an AUROC curve value of 0.90 (95% CI: 0.82-0.97; P < .001). Measurement of serum keratin 18 fragments or alanine aminotransferase did not add value to TE or MRI for identifying nonalcoholic steatohepatitis.

CONCLUSIONS

MRE and PDFF methods have higher diagnostic performance in noninvasive detection of liver fibrosis and steatosis in patients with NAFLD than TE and CAP methods. MRI-based noninvasive assessment of liver fibrosis and steatosis is a potential alternative to liver biopsy in clinical practice. UMIN Clinical Trials Registry No. UMIN000012757.

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Affiliation(s)

Kento Imajo Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Takaomi Kessoku Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Yasushi Honda Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Wataru Tomeno Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Yuji Ogawa Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Hironori Mawatari Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Koji Fujita Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Masato Yoneda Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Masataka Taguri Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Hideyuki Hyogo Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
Yoshio Sumida Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto, Japan
Masafumi Ono Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan
Yuichiro Eguchi Division of Hepatology, Saga Medical School, Liver Center, Saga, Japan
Tomio Inoue Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Takeharu Yamanaka Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Koichiro Wada Department of Pharmacology, Shimane University Faculty of Medicine, Izumo, Shimane, Japan
Satoru Saito Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
Atsushi Nakajima Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

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Wang Q, Du J, Yu P, Bai B, Zhao Z, Wang S, Zhu J, Feng Q, Gao Y, Zhao Q, Liu C. Hepatic steatosis depresses alpha-1-antitrypsin levels in human and rat acute pancreatitis. Sci Rep 2015;5:17833. [PMID: 26634430 PMCID: PMC4669469 DOI: 10.1038/srep17833] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 11/06/2015] [Indexed: 12/11/2022] Open

Martinez-Lopez N, Singh R. Autophagy and Lipid Droplets in the Liver. Annu Rev Nutr 2015;35:215-37. [PMID: 26076903 PMCID: PMC7909712 DOI: 10.1146/annurev-nutr-071813-105336] [Citation(s) in RCA: 256] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]

Liu M, Xu L, Yin L, Qi Y, Xu Y, Han X, Zhao Y, Sun H, Yao J, Lin Y, Liu K, Peng J. Potent effects of dioscin against obesity in mice. Sci Rep 2015;5:7973. [PMID: 25609476 PMCID: PMC4302319 DOI: 10.1038/srep07973] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 12/12/2014] [Indexed: 12/11/2022] Open

Cengiz M, Yasar DG, Ergun MA, Akyol G, Ozenirler S. The role of interleukin-6 and interleukin-8 gene polymorphisms in non-alcoholic steatohepatitis. HEPATITIS MONTHLY 2014;14:e24635. [PMID: 25737730 PMCID: PMC4329235 DOI: 10.5812/hepatmon.24635] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 11/25/2014] [Accepted: 12/07/2014] [Indexed: 12/11/2022]

Abstract

BACKGROUND

Genetic polymorphisms may play role in the pathophysiology of nonalcoholic steatohepatitis (NASH).

OBJECTIVES

We purposed to assess the role of interleukin 6 (IL 6) and interleukin 8 (IL 8) gene polymorphisms in the pathogenesis of NASH.

PATIENTS AND METHODS

Consecutive patients with biopsy proven NASH and age- and gender-matched healthy individuals with normal liver function tests and normal ultrasonography were enrolled in the study. Histopathological findings were recorded according to nonalcoholic fatty liver disease activity score (NAS). Patients were classified according to fibrosis scores as fibrosis score < 2 (mild fibrosis group) and fibrosis score ≥ 2 (significant fibrosis group). Blood samples were collected and genomic DNA isolation kit was used to evaluate genetic polymorphisms.

RESULTS

Of thirty-eight patients, 27 (71%) were in mild fibrosis group and 11 (29%) in significant fibrosis group. Thirty-eight age- and gender-matched healthy controls were enrolled in the study. The frequencies of genotypes G/C and G/G of IL 6 among the NASH group and healthy controls were 39.5% and 60.5% vs. 53.6% and 46.4%, respectively (P = 0.32). The frequencies of the genotypes of IL 8 among the NASH group were 47.2%, 44.6%, and 8.2% for T/T, A/T, and A/A, and in healthy controls were 50%, 28.6% and 21.4%, respectively, (P = 0.568). The differences between IL 8 gene T/A and T/T genotypes were not significant statistically (P > 0.05). However, the frequency of A/A genotype in significant fibrosis group was higher than the mild fibrosis group (P = 0.0016). The differences of -251 A/T polymorphism in the IL 8 and -174 C/G polymorphism in the IL 6 were not statistically significant between fibrosis groups (P > 0.05).

CONCLUSIONS

IL6 and IL8 gene polymorphisms have no role in NASH pathogenesis and liver fibrosis process, but presence of the A/A genotype in the IL8 gene is associated with disease progression.

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Leach NV, Dronca E, Vesa SC, Sampelean DP, Craciun EC, Lupsor M, Crisan D, Tarau R, Rusu R, Para I, Grigorescu M. Serum homocysteine levels, oxidative stress and cardiovascular risk in non-alcoholic steatohepatitis. Eur J Intern Med 2014;25:762-7. [PMID: 25262992 DOI: 10.1016/j.ejim.2014.09.007] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Revised: 08/09/2014] [Accepted: 09/08/2014] [Indexed: 02/07/2023]

Abstract

INTRODUCTION

Hyperhomocysteinemia is considered an independent risk factor for cardiovascular disease. Oxidative stress is one of the major pathogenic mechanisms in non-alcoholic fatty liver disease and atherosclerosis.

AIM

Our study aimed to evaluate serum homocysteine levels and oxidative stress in patients with biopsy-proven non-alcoholic steatohepatitis and possible association with cardiovascular risk measured by carotid artery intima-media thickness (c-IMT).

PATIENTS AND METHODS

50 patients with non-alcoholic steatohepatitis and 30 healthy controls, age and gender matched, were recruited. Lipid profile, liver biochemical markers, serum homocysteine, vitamins B6 and B12, folic acid, glutathione (reduced and total), erythrocyte superoxide dismutase, whole blood glutathione peroxidase, malondialdehyde and carotid intima-media thickness were assayed.

RESULTS

Patients had an altered lipid profile and liver biochemical markers; carotid intima-media thickness and serum homocysteine levels were significantly higher compared to controls, but there were no differences in folate, B12 and B6 vitamins levels. Patients had significantly lower levels of glutathione peroxidase activity, total and reduced glutathione and higher levels of malondialdehyde, but unchanged superoxide dismutase activity compared to control group. Also, serum homocysteine level showed significant positive correlation with waist circumference, body mass index, free cholesterol, triglycerides, LDL-cholesterol, amino transferases and negative correlation with reduced and total glutathione, superoxide dismutase and γ-GT.

CONCLUSION

Non-alcoholic steatohepatitis is an independent cardiovascular risk factor, associated with elevated homocysteine levels, oxidative stress and c-IMT. c-IMT could be used as an indicator of early atherosclerotic changes initiated by dyslipidemia and oxidative stress, while higher level of homocysteine might be an effect of liver damage.

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Haflidadottir S, Jonasson JG, Norland H, Einarsdottir SO, Kleiner DE, Lund SH, Björnsson ES. Long-term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease. BMC Gastroenterol 2014;14:166. [PMID: 25260964 PMCID: PMC4182763 DOI: 10.1186/1471-230x-14-166] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 09/23/2014] [Indexed: 02/06/2023] Open

Abstract

BACKGROUND

Few studies have compared the prognosis and liver-related mortality in patients with NAFLD (nonalcoholic fatty liver disease) and AFLD (alcoholic fatty liver disease). We aimed to investigate the etiology and liver-related mortality of patients with liver biopsy verified fatty liver disease in a population based setting.

METHODS

In this retrospective study, all patients who underwent a liver biopsy 1984-2009 at the National University Hospital of Iceland were identified through a computerized pathological database with the code for fatty liver. Only patients with NAFLD and AFLD were included and medical records reviewed. The patients were linked to the Hospital Discharge Register, the Causes of Death Registry and Centre for Addiction Medicine.

RESULTS

A total of 151 had NAFLD and 94 AFLD with median survival of 24 years and 20 years, respectively (p = NS). A total of 10/151 (7%) patients developed cirrhosis in the NAFLD group and 19/94 (20%) in AFLD group (p = 0.03). The most common cause of death in the NAFLD group was cardiovascular disease (48%). Liver disease was the most common cause of death in the AFLD group (36%), whereas liver-related death occurred in 7% of the NAFLD group. The mean liver-related death rate among the general population during the study period was 0.1% of all deaths. There was a significantly worse survival for patients in the AFLD group compared to the NAFLD group after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.16, p = 0.009). The survival for patients with moderate to severe fibrosis was significantly worse than for patients with mild fibrosis after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.09, p = 0.01).

CONCLUSIONS

Patients with fatty liver disease showed a markedly higher risk of developing liver-related death compared to the general population. The AFLD group had higher liver-related mortality and had a worse survival than the NAFLD group. Patients with more severe fibrosis at baseline showed a worse survival than patients with none or mild fibrosis at baseline.

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Sato R, Kishiwada M, Kuriyama N, Azumi Y, Mizuno S, Usui M, Sakurai H, Tabata M, Yamada T, Isaji S. Paradoxical impact of the remnant pancreatic volume and infectious complications on the development of nonalcoholic fatty liver disease after pancreaticoduodenectomy. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014;21:562-572. [PMID: 24824077 DOI: 10.1002/jhbp.115] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]

Microbiota and nonalcoholic steatohepatitis. Semin Immunopathol 2013;36:115-32. [PMID: 24337650 DOI: 10.1007/s00281-013-0404-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 10/15/2013] [Indexed: 02/07/2023]

Imajo K, Yoneda M, Kessoku T, Ogawa Y, Maeda S, Sumida Y, Hyogo H, Eguchi Y, Wada K, Nakajima A. Rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Int J Mol Sci 2013;14:21833-57. [PMID: 24192824 PMCID: PMC3856038 DOI: 10.3390/ijms141121833] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 10/14/2013] [Accepted: 10/21/2013] [Indexed: 02/06/2023] Open

Arinc H, Sarli B, Baktir AO, Saglam H, Demirci E, Dogan Y, Kurtul S, Karaman H, Erden A, Karaman A. Serum gamma glutamyl transferase and alanine transaminase concentrations predict endothelial dysfunction in patients with non-alcoholic steatohepatitis. Ups J Med Sci 2013;118:228-34. [PMID: 23829707 PMCID: PMC4190884 DOI: 10.3109/03009734.2013.814734] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open

Fukunishi S, Sujishi T, Takeshita A, Ohama H, Tsuchimoto Y, Asai A, Tsuda Y, Higuchi K. Lipopolysaccharides accelerate hepatic steatosis in the development of nonalcoholic fatty liver disease in Zucker rats. J Clin Biochem Nutr 2013;54:39-44. [PMID: 24426189 PMCID: PMC3882483 DOI: 10.3164/jcbn.13-49] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 08/16/2013] [Indexed: 02/06/2023] Open

Ogawa Y, Imajo K, Yoneda M, Kessoku T, Tomeno W, Shinohara Y, Kato S, Mawatari H, Nozaki Y, Fujita K, Kirikoshi H, Maeda S, Saito S, Wada K, Nakajima A. Soluble CD14 levels reflect liver inflammation in patients with nonalcoholic steatohepatitis. PLoS One 2013;8:e65211. [PMID: 23762319 PMCID: PMC3676404 DOI: 10.1371/journal.pone.0065211] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2012] [Accepted: 04/24/2013] [Indexed: 01/08/2023] Open

Kelishadi R, Farajian S, Mirlohi M. Probiotics as a novel treatment for non-alcoholic Fatty liver disease; a systematic review on the current evidences. HEPATITIS MONTHLY 2013;13:e7233. [PMID: 23885277 PMCID: PMC3719124 DOI: 10.5812/hepatmon.7233] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 08/01/2012] [Accepted: 08/22/2012] [Indexed: 12/11/2022]

Del Ben M, Baratta F, Polimeni L, Angelico F. Non-alcoholic fatty liver disease and cardiovascular disease: epidemiological, clinical and pathophysiological evidences. Intern Emerg Med 2012;7 Suppl 3:S291-S296. [PMID: 23073870 DOI: 10.1007/s11739-012-0819-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]

Dal Rhee S, Kim CH, Seon Park J, Hoon Jung W, Bum Park S, Youn Kim H, Hwan Bae G, Jan Kim T, Young Kim K. Carbenoxolone prevents the development of fatty liver in C57BL/6-Lep ob/ob mice via the inhibition of sterol regulatory element binding protein-1c activity and apoptosis. Eur J Pharmacol 2012;691:9-18. [DOI: 10.1016/j.ejphar.2012.06.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Revised: 06/11/2012] [Accepted: 06/13/2012] [Indexed: 10/28/2022]

Imajo K, Fujita K, Yoneda M, Shinohara Y, Suzuki K, Mawatari H, Takahashi J, Nozaki Y, Sumida Y, Kirikoshi H, Saito S, Nakamuta M, Matsuhashi N, Wada K, Nakajima A. Plasma free choline is a novel non-invasive biomarker for early-stage non-alcoholic steatohepatitis: A multi-center validation study. Hepatol Res 2012;42:757-66. [PMID: 22780848 DOI: 10.1111/j.1872-034x.2012.00976.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]