Hepatitis B virus surface proteins accelerate cholestatic injury and tumor progression in Abcb4-knockout mice

Zahner, Daniel; Glimm, Hannah; Matono, Tomomitsu; Churin, Y; Herebian, Diran; Mayatepek, Ertan; Köhler, Kernt; Gattenlöhner, Stefan; Stinn, Anne; Tschuschner, A; Roderfeld, M; Roeb, Elke

doi:10.18632/oncotarget.15003

Cited by 5 publications

(8 citation statements)

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“…The reduced expression of AGPAT1 , GPAT1 , MGAT1 , and DGAT2 implicated that FFAs cannot be utilized for TAG synthesis. But increased free fatty acid (FFA) levels in parallel with reduction a of TAG synthesis and accumulation along with increased lipolysis during cholestasis seems to facilitate the acceleration of liver injury ( Zahner et al, 2017 ).…”

Section: Lipogenic Markers and Triacylglycerol Synthesismentioning

confidence: 99%

Fructose and Non-Alcoholic Steatohepatitis

Roeb

Weiskirchen

2021

Front. Pharmacol.

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Background: The excessive consumption of free sugars is mainly responsible for the high prevalence of obesity and metabolic syndrome in industrialized countries. More and more studies indicate that fructose is involved in the pathophysiology and also in the degree of disease of non-alcoholic fatty liver disease (NAFLD). In epidemiologic studies, energy-adjusted higher fructose consumption correlates with NAFLD in overweight adults. In addition to glucose, fructose, as an equivalent component of conventional household sugar, appears to have negative metabolic effects in particular due to its exclusive hepatic metabolism. Liver-related mortality is strictly associated with the degree of fibrosis, whereas the most common cause of death in patients suffering from NAFLD and non-alcoholic steatohepatitis (NASH) are still cardiovascular diseases. In this review article, we have summarized the current state of knowledge regarding a relationship between fructose consumption, liver fibrosis and life expectancy in NASH.Method: Selective literature search in PubMed using the keywords ‘non-alcoholic fatty liver’, ‘fructose’, and ‘fibrosis’ was conducted.Results: The rate of overweight and obesity is significantly higher in both, adult and pediatric NASH patients. The consumption of free sugars is currently three times the maximum recommended amount of 10% of the energy intake. The current literature shows weight gain, negative effects on fat and carbohydrate metabolism and NASH with hypercaloric intake of fructose.Conclusions: Excessive fructose consumption is associated with negative health consequences. Whether this is due to an excess of energy or the particular metabolism of fructose remains open with the current study situation. The urgently needed reduction in sugar consumption could be achieved through a combination of binding nutritional policy measures including taxation of sugary soft drinks. Previous studies suggest that diet-related fructose intake exceeding the amount contained in vegetables and fruits lead to an increase of hepatic lipogenesis. Thus, further studies to clarify the protective contribution of low-fructose intake to positively influence NAFLD in industrial population are urgently required.

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Section: Lipogenic Markers and Triacylglycerol Synthesismentioning

confidence: 99%

Fructose and Non-Alcoholic Steatohepatitis

Roeb

Weiskirchen

2021

Front. Pharmacol.

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“…Similarly, biliary diseases might even be attributed to or caused by HBV infection [ 39 ]. We have reported earlier that HBs can enhance cholestatic liver injury, fibrosis, and tumorigenesis in Abcb4 knockout mice [ 23 ]. Therefore, there is an urgent need for medical correction of cholestasis at the earliest form of fatty liver diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies indicated the beneficial effects of lipid storage and loss of TAG storage capacity being critically linked to lipotoxicity, which has been shown to exacerbate liver injury [ 46 ]. Therefore, increased FFA levels in parallel with suppression of TAG synthesis and storage along with enhanced lipolysis pathways in HBs/Abcb4 −/− mice might also contribute to the acceleration of liver injury [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, cholesterol uptake might be affected in HBs/Abcb4 −/− mice (Fig. 1h ) as elevated plasma bile acid levels are a characteristic hallmark in Abcb4 −/− mice [ 48 ] as well as in HBs/Abcb4 −/− mice [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the authors reported that liver injury was critically linked to impaired lipid homeostasis, which was ameliorated by norUDCA treatment and additionally by dietary intervention in Abcb4 −/− mice under HFD. Similarly, we previously reported that hepatitis B virus surface proteins could accelerate cholestatic liver injury and tumor progression in Abcb4 −/− mice reflecting a model of simultaneous liver damage with enhanced carcinogenesis [ 23 ]. Based on these findings, the present study was designed to investigate the effect of Abcb4 knockout-induced cholestasis on lipid metabolism in HBs transgenic mice.…”

Section: Introductionmentioning

confidence: 91%

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Cholestasis impairs hepatic lipid storage via AMPK and CREB signaling in hepatitis B virus surface protein transgenic mice

Irungbam

Roderfeld

Glimm

et al. 2020

Laboratory Investigation

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Clinical studies demonstrated that nonalcoholic steatohepatitis is associated with liver-related outcomes in chronic hepatitis B. Furthermore, primary biliary fibrosis and biliary atresia occurred in patients with HBV infection. Interestingly, hepatitis B virus surface protein (HBs) transgenic mice spontaneously develop hepatic steatosis. Our aim is to investigate the effect of Abcb4 knockout-induced cholestasis on liver steatosis in HBs transgenic mice. Hybrids of HBs transgenic and Abcb4−/− mice were bred on the BALB/c genetic background. Lipid synthesis, storage, and catabolism as well as proteins and genes that control lipid metabolism were analyzed using HPTLC, qPCR, western blot, electrophoretic mobility shift assay (EMSA), lipid staining, and immunohistochemistry. Hepatic neutral lipid depots were increased in HBs transgenic mice and remarkably reduced in Abcb4−/− and HBs/Abcb4−/− mice. Similarly, HPTLC-based quantification analyses of total hepatic lipid extracts revealed a significant reduction in the amount of triacylglycerols (TAG), while the amount of free fatty acids (FFA) was increased in Abcb4−/− and HBs/Abcb4−/− in comparison to wild-type and HBs mice. PLIN2, a lipid droplet-associated protein, was less expressed in Abcb4−/− and HBs/Abcb4−/−. The expression of genes-encoding proteins involved in TAG synthesis and de novo lipogenesis (Agpat1, Gpat1, Mgat1, Dgat1, Dgat2, Fasn, Hmgcs1, Acc1, Srebp1-c, and Pparγ) was suppressed, and AMPK and CREB were activated in Abcb4−/− and HBs/Abcb4−/− compared to wild-type and HBs mice. Simulating cholestatic conditions in cell culture resulted in AMPK and CREB activation while FASN and PLIN2 were reduced. A concurrent inhibition of AMPK signaling revealed normal expression level of FASN and PLIN2, suggesting that activation of AMPK–CREB signaling regulates hepatic lipid metabolism, i.e. synthesis and storage, under cholestatic condition. In conclusions, in vivo and mechanistic in vitro data suggest that cholestasis reduces hepatic lipid storage via AMPK and CREB signaling. The results of the current study could be the basis for novel therapeutic strategies as NASH is a crucial factor that can aggravate chronic liver diseases.

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Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4 Mice

Helmrich

Roderfeld

Baier

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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Antagonization of endocannabinoid receptor 1 by rimonabant ameliorated metabolic, inflammatory, and carcinogenesis-associated processes, as well as serum bile acids in Abcb4-knockout mice. This leads to an improvement of cholestasis and reduced hepatic pathogenesis. BACKGROUND & AIMS:The endocannabinoid system is involved in the modulation of inflammatory, fibrotic, metabolic, and carcinogenesis-associated signaling pathways via cannabinoid receptor (CB)1 and CB2. We hypothesized that the pharmacologic antagonization of CB1 receptor improves cholestasis in Abcb4 -/mice. METHODS:After weaning, male Abcb4 -/mice were treated orally with rimonabant (a specific antagonist of CB1) or ACEA (an agonist of CB1) until up to 16 weeks of age Q10 . Liver tissue and serum were isolated and examined by means of serum analysis, quantitative reverse-transcription polymerase chain reaction Q11 , Western blot, immunohistochemistry, and enzyme function. Untreated Abcb4 -/and BALB/ Q12 c wild-type mice served as controls. RESULTS: Cholestasis-induced symptoms such as liver damage, bile duct proliferation, and enhanced circulating bile acids were improved by CB1 antagonization. Rimonabant treatment also improved PEPCK Q13 expression and reduced inflammation and the acute-phase response. The carcinogenesis-associated c-Jun N-terminal kinase/c-JUN and signal transducer and activator of transcription 3 signaling pathways activated in Abcb4 -/mice were reduced to wild-type level by CB1 antagonization. CONCLUSIONS:We showed a protective effect of oral CB1 antagonization in chronic cholestasis using the established Abcb4 -/model. Our results suggest that pharmacologic antagonization of the CB1 receptor could have a therapeutic benefit in cholestasis-associated metabolic changes, liver damage, inflammation, and carcinogenesis.

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Hepatitis B virus surface proteins accelerate cholestatic injury and tumor progression in Abcb4-knockout mice

Cited by 5 publications

References 49 publications

Fructose and Non-Alcoholic Steatohepatitis

Fructose and Non-Alcoholic Steatohepatitis

Cholestasis impairs hepatic lipid storage via AMPK and CREB signaling in hepatitis B virus surface protein transgenic mice

Pharmacologic Antagonization of Cannabinoid Receptor 1 Improves Cholestasis in Abcb4 Mice

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