From NAFLD to NASH to cirrhosis—new insights into disease mechanisms

Wree, Alexander; Broderick, Lori; Canbay, Ali; Hoffman, Hal M.; Feldstein, Ariel E.

doi:10.1038/nrgastro.2013.149

Cited by 538 publications

(446 citation statements)

References 114 publications

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Section: Discussionmentioning

confidence: 99%

“…An increase in hepatocyte cell death by apoptosis is typically present in patients with NAFLD and in experimental models of this disease, 31,32 The two fundamental pathways of apoptosis, the extrinsic (death receptor-mediated) and intrinsic (organelleinitiated) pathways, are involved. 31 The results of the current study demonstrate that selective deletion of Bid in hepatocytes protects from DEN-induced tumorigenesis. Due to the fact that the initial cellular damage occurring within the first days of DEN injection is known to be of major importance in HCC induction, 7 we assessed the livers of mice 48 h after DEN injection and observed that Bid Δhep mouse livers were protected from the hepatocyte cell death, compensatory proliferation and inflammatory changes that typically result from DEN administration.…”

Section: Discussionmentioning

confidence: 99%

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Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

et al. 2015

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Liver cancer is a major health-care concern and its oncogenic mechanisms are still largely unclear. Persistent hepatocyte cell death is a common feature among various chronic liver diseases, the blocking of which presents as logical treatment. Therefore, we aimed at investigating tumor development in mice with hepatocyte-specific Bid depletion -a BH3-only Bcl-2 family member that amplifies apoptotic death signals. Hepatocyte-specific conditional Bid-knockout mice (Bid Δhep ) were injected with 25 mg/kg diethylnitrosamine (DEN) at 14 days of age, and liver tumorigenesis was investigated 9 months later. Additionally, different models of acute liver injury were used including: acute high-dose DEN challenge, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet and carbon tetrachloride (CCL4) injection. Bid Δhep mice developed significantly fewer tumors, showed smaller maximal and average tumor size and reduced tumor incidence. In the acute DEN model, 48 h post injection we observed a significant reduction in liver injury in Bid Δhep animals, assessed via serum transaminases and liver histopathology. Furthermore, TNF-α, IL-1ß, cJUN and IL-6 mRNA expression was reduced. These findings were accompanied by reduced compensatory hepatocyte proliferation in Bid Δhep mice when compared with controls by immunohistochemistry for Ki67 and proliferating cell nuclear antigen 48 h after DEN injection. In the acute CCL4 model, Bid Δhep mice displayed reductions in liver injury and inflammation when compared with controls. No differences in liver injury and serum bilirubin levels were detected in Bid Δhep and Bid flo/flo mice fed with DDC, which induces bile duct injury and a ductular reaction. Our study demonstrates that in DEN-induced hepatocellular carcinoma, the inhibition of hepatocyte death pathways through Bid deletion protects animals from tumorigenesis. These results suggest that reducing hepatocyte cell death, liver inflammation and compensatory proliferation has a stronger beneficial effect than the potential side effect of enhancing tumor cell survival.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

et al. 2015

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“…As with GSC and GDD the difference between the two is based on the interplay of host genetics and immunology, to the presence of fat in the liver. NASH is associated with defined genes, which is not associated with NAFLD [48,49].…”

Section: Pathophysiologymentioning

confidence: 99%

Gadolinium toxicity and treatment

Ramalho

Jay

et al. 2016

Magnetic Resonance Imaging

103

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a b s t r a c t a r t i c l e i n f oGadolinium based contrast agents (GBCAs) play an important role in the diagnostic evaluation of many patients. The safety of these agents has been once again questioned after gadolinium deposits were observed and measured in brain and bone of patients with normal renal function. This retention of gadolinium in the human body has been termed "gadolinium storage condition". The long-term and cumulative effects of retained gadolinium in the brain and elsewhere are not as yet understood. Recently, patients who report that they suffer from chronic symptoms secondary to gadolinium exposure and retention created gadolinium-toxicity on-line support groups. Their self-reported symptoms have recently been published. Bone and joint complaints, and skin changes were two of the most common complaints. This condition has been termed "gadolinium deposition disease". In this review we will address gadolinium toxicity disorders, from acute adverse reactions to GBCAs to gadolinium deposition disease, with special emphasis on the latter, as it is the most recently described and least known.

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“…The prevalence of NAFLD is estimated to range from 25 to 37% of the general population (1)(2)(3)(4), and it constitutes a common etiological factor of chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH) is a progressive form of NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice

Kawaguchi

Ueno

Nogata

et al. 2016

International Journal of Molecular Medicine

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Abstract. Whole-wheat intake is known to reduce the risk of metabolic syndrome. However, the active component remains unclear. Recently, we identified bioactive peptides [leucinearginine-proline (LRP) and leucine-glutamine-proline (LQP)] from wheat bran autolytic hydrolysate. The present study aimed to investigate the effects of LRP and LQP on non-alcoholic steatohepatitis (NASH) in a mouse model. We also evaluated the effects of these peptides on oxidative stress and on the AMP-activated protein kinase (AMPK) signaling pathway, two major pathogenic factors of NASH. Seven-week-old male C57BL/6 mice were fed a high-fat diet for 10 weeks and administered water supplemented with 0.05% LRP, 0.20% LRP, 0.05% LQP, or 0.20% LQP (each n=5) or distilled water (control; n=5) ad libitum. Oxidative stress was evaluated by measuring the serum levels of diacron reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP). Hepatic expression of phosphorylated AMPK and phosphorylated acetyl-CoA carboxylase (ACC) were evaluated by immunoblotting. The result showed that non-alcoholic fatty liver disease activity score was significantly decreased in all types of treatment. Serum d-ROM levels were significantly decreased in the 0.20% LRP group, but not in the 0.05% LRP, 0.05% LQP, and 0.20% LQP groups. Serum BAP levels were significantly increased in the 0.05% LRP and 0.20% LRP groups, but not in the 0.05% LQP and 0.20% LQP groups. Immunoblotting analysis revealed that the expression of phospho-AMPK was increased whereas that of phospho-ACC was decreased in the 0.20% LQP group. In conclusion, we demonstrated that both LRP and LQP alleviated the severity of NASH in a high-fat diet-induced NASH mouse model. In addition, we showed that LRP and LQP modulated oxidative stress and upregulated AMPK/ACC, respectively. Thus, LRP and LQP may constitute clinically applicable therapeutic agents for NASH. IntroductionNon-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. The prevalence of NAFLD is estimated to range from 25 to 37% of the general population (1-4), and it constitutes a common etiological factor of chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH) is a progressive form of NAFLD. Patients with NASH have a high risk of life-threatening complications, including cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma (5,6). In addition, NASH is predicted to become the leading cause of liver transplantation in the USA by the year 2020 (2). Thus, NAFLD/NASH is becoming a major social issue worldwide.The first-line therapy for NASH is life-style intervention. Although diet and exercise alleviate the severity of NASH, long-term adherence to life-style interventions is poor (7,8). Pioglitazone, an insulin-sensitizing anti-diabetic agent, leads to metabolic and histologic improvement in patients with NASH (9). However, the indication of pioglitazone is restricted to NASH patients with diabetes mellitus (10). Furthermore, severe liver disease is a contrai...

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From NAFLD to NASH to cirrhosis—new insights into disease mechanisms

Cited by 538 publications

References 114 publications

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

Hepatocyte-specific Bid depletion reduces tumor development by suppressing inflammation-related compensatory proliferation

Gadolinium toxicity and treatment

Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice

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