Pivotal Role of TNF-α in the Development and Progression of Nonalcoholic Fatty Liver Disease in a Murine Model

Kakino, Satomi; Ohki, Tsuyoshi; Nakayama, Hitomi; Yuan, Xiahong; Otabe, Shuichi; Hashinaga, Toshihiko; Wada, Nobuhiko; Kurita, Yayoi; Tanaka, Kayo; Hara, Kimihiko; Soejima, Eri; Tajiri, Yuji; Yamada, Kentaro

doi:10.1055/s-0043-118666

Cited by 118 publications

(91 citation statements)

References 41 publications

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“…The supplementation of 5% CO could also elevate the circulated levels of tumor necrosis factor-alpha (TNF-α) in HF diet-fed rats ( Figure 3C). Kakino et al (2018) have suggested that TNF-α plays a pivotal role in the development and progression of NAFLD by the association with lipid metabolism and inflammation in the liver [18], which is consistent with our finding in the present study that diets supplemented with 5% CO may induce liver damage. Moreover, as shown in Figure 4, rats fed with HF diets for 8 weeks exhibit a significant increase in hepatic ( Figure 4A) and fecal ( Figure 4B) TC levels.…”

Section: Effects Of Hc Lc and Co On Hepatic And Fecal Lipid Responssupporting

confidence: 93%

Comparative Effects and Mechanisms of Chitosan and Its Derivatives on Hypercholesterolemia in High-Fat Diet-Fed Rats

Chiu¹,

Yen

Liu

et al. 2019

IJMS

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The present study investigated and compared the effects of different molecular weights of chitosan (high molecular weight chitosan (HC) and low molecular weight chitosan (LC)) and its derivatives (chitosan oligosaccharide (CO)) on cholesterol regulation in high-fat (HF) diet-fed rats. A diet supplementation of 5% HC, 5% LC, or 5% CO for 8 weeks showed hypocholesterolemic potential in HF diet-fed rats. Unexpectedly, a 5% CO-supplemented diet exerted hepatic damage, producing increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and tumor necrosis factor-alpha (TNF-α). The supplementation of HC and LC, unlike CO, significantly decreased the hepatic total cholesterol (TC) levels and increased the fecal TC levels in HF diet-fed rats. The hepatic protein expression of the peroxisome proliferator-activated receptor-α (PPARα) in the HF diet-fed rats was markedly decreased, which could be significantly reversed by both HC and LC, but not CO, supplementation. Unlike the supplementation of CO, both HC and LC supplementation could effectively reverse the HF-inhibited/induced gene expressions of the low-density lipoprotein receptor (LDLR) and cholesterol 7α-hydroxylase (CYP7A1), respectively. The upregulated intestinal acyl-CoA cholesterol acyltransferase 2 (ACAT2) protein expression in HF diet-fed rats could be reversed by HC and LC, but not CO, supplementation. Taken together, a supplementation of 5% CO in HF diet-fed rats may exert liver damage via a higher hepatic cholesterol accumulation and a higher intestinal cholesterol uptake. Both HC and LC effectively ameliorated the hypercholesterolemia and regulated cholesterol homeostasis via the activation and inhibition of hepatic (AMPKα and PPARα) and intestinal (ACAT2) cholesterol-modulators, respectively, as well as the modulation of downstream signals (LDLR and CYP7A1).

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Section: Effects Of Hc Lc and Co On Hepatic And Fecal Lipid Responssupporting

confidence: 93%

Comparative Effects and Mechanisms of Chitosan and Its Derivatives on Hypercholesterolemia in High-Fat Diet-Fed Rats

Chiu¹,

Yen

Liu

et al. 2019

IJMS

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show abstract

“…Thus, it is not surprising that TNF sensing by hepatocytes promotes hepatocyte cell death and hepatocyte proliferation (67), and as such directly contributes to NAFLD pathogenesis (68). Further, deletion of TNF in experimental mouse models of NAFLD correlates with decreased steatosis, fibrosis and improved glucose tolerance (69).…”

Section: Macrophages and Proinflammatory Cytokine Productionmentioning

confidence: 99%

Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack

et al. 2019

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“…36 In the rat models, previous experiments implied a pivot role of TNF-α in the pathogenesis of NASH. 11 Administration of infliximab could reverse diet-induced hepatic steatosis in rats. 17 18 The sonographic stage of NAFLD also correlated with serum levels of TNF-α in individuals with morbid obesity.…”

Section: Discussionmentioning

confidence: 99%

Antitumour necrosis factor-α agents and development of new-onset cirrhosis or non-alcoholic fatty liver disease: a retrospective cohort

Tang

Dufour

Chen

et al. 2020

BMJ Open Gastroenterol

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ObjectiveElevated tumour necrosis factor (TNF)-α has been implicated in the progression of liver fibrosis and pathogenesis of non-alcoholic fatty liver disease (NAFLD). We aim to investigate the impact of anti-TNF-α agents on the development of cirrhosis and NAFLD.DesignThis retrospective cohort study used a US claims database between 1 January 2010 and 31 December 2016. We identified adult patients with ankylosing spondylitis, inflammatory bowel disease, psoriatic arthritis or rheumatoid arthritis. Anti-TNF-α agents of interest included adalimumab, certolizumab, etanercept, golimumab and infliximab. The primary composite outcome was the development of new-onset cirrhosis, NAFLD or non-alcoholic steatohepatitis (NASH). The secondary outcomes were the development of (1) cirrhosis and (2) NAFLD or NASH. Propensity score for anti-TNF-α agent use was generated by logistic regression. Cox proportional hazard models adjusting for the propensity score were used with regard to time-varying anti-TNF-α agent exposure.ResultsThis study included 226 555 incident patients with immune-related diseases. During the median 1.5 years follow-up, there was an increased hazard with anti-TNF-α agent use in regard to liver outcomes (composite outcome HR: 1.47, 95% CI 1.27 to 1.70; cirrhosis HR 1.47, 95% CI 0.96 to 2.23; NAFLD or NASH HR 1.53, 95% CI 1.32 to 1.77). The composite outcome hazard was increased for each immune-related disease (HR 1.25–1.90).ConclusionIn the short term, we did not observe a beneficial effect of anti-TNF-α agent use for development of cirrhosis, NAFLD or NASH in patients with immune-related diseases.

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Pivotal Role of TNF-α in the Development and Progression of Nonalcoholic Fatty Liver Disease in a Murine Model

Cited by 118 publications

References 41 publications

Comparative Effects and Mechanisms of Chitosan and Its Derivatives on Hypercholesterolemia in High-Fat Diet-Fed Rats

Comparative Effects and Mechanisms of Chitosan and Its Derivatives on Hypercholesterolemia in High-Fat Diet-Fed Rats

Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack

Antitumour necrosis factor-α agents and development of new-onset cirrhosis or non-alcoholic fatty liver disease: a retrospective cohort

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