Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease

Puls, Florian; Goldschmidt, Imeke; Bantel, Heike; Agné, Clemens; Bröcker, Verena; Dämmrich, Maximilian Ernst; Lehmann, Ulrich; Berrang, Jens; Pfister, Eva‐Doreen; Kreipe, Hans; Baumann, Ulrich

doi:10.1016/j.jhep.2013.05.018

Cited by 50 publications

(64 citation statements)

References 15 publications

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“…Genetically enhancing autophagy by overexpressing Atg7 could alleviate hepatic steatosis induced by a high-fat diet [39]. Carbamazepine, an FDA-approved antiepileptic drug, can alleviate fatty liver by inducing autophagy [40]. In contrast, loss of autophagy in vitro or in vivo increases lipid accumulation in cells and in liver [2,4,19].…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy

Yang

Rozenfeld

et al. 2014

Free Radical Biology and Medicine

117

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Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy.

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Section: Discussionmentioning

confidence: 99%

Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy

Yang

Rozenfeld

et al. 2014

Free Radical Biology and Medicine

117

View full text Add to dashboard Cite

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“…Each half of the dimer is composed of three polypeptide chains (termed A α , B β , and γ ) that are assembled in the ER. Several mutations in the fibrinogen gamma chain have been reported (fibrinogen Brescia, Aguadilla, AI DuPont, and Angers) that are associated with fibrinogen storage disease, an autosomal-dominant disorder that is characterized by low circulating plasma fibrinogen levels and abnormal accumulation of fibrinogen components within the hepatocyte ER [34, 35]. Reminiscent of ATD-associated liver disease, patients with fibrinogen storage disease display characteristics of both loss of function (hypofibrinogenemia) and gain-of-toxic function (accumulation of fibrinogen components in ER).…”

Section: Potential Role For Autophagy-enhancing Strategies In Othementioning

confidence: 99%

“…These results suggest that the mutant fibrinogen Aguadilla behaves similarly to mutant ATZ in the fact that it accumulates within the secretory pathway, has a tendency to polymerize/aggregate, and is degraded by proteasomal and autophagic mechanisms. Based on these findings as well as work by the Perlmutter group that demonstrated amelioration of experimental ATD-associated liver disease by the autophagy-enhancing drug carbamazepine, Puls et al recently conducted a small study of two patients with fibrinogen storage disease in which they found that administration of carbamazepine at antiepileptic doses was associated with normalization of alanine-aminotransferase and reduction of markers of apoptosis and necrosis [35]. …”

Section: Potential Role For Autophagy-enhancing Strategies In Othementioning

confidence: 99%

Capitalizing on the Autophagic Response for Treatment of Liver Disease Caused by Alpha-1-Antitrypsin Deficiency and Other Genetic Diseases

Chu

Perlmutter

Wang

2014

BioMed Research International

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Alpha-1-antitrypsin deficiency (ATD) is one of the most common genetic causes of liver disease and is a prototype of liver diseases caused by the pathologic accumulation of aggregated mutant alpha-1-antitrypsin Z (ATZ) within liver cells. In the case of ATD-associated liver disease, the resulting “gain-of-function” toxicity can lead to serious clinical manifestations, including cirrhosis and hepatocellular carcinoma. Currently, the only definitive therapy for ATD-associated liver disease is liver transplantation, but recent efforts have demonstrated the exciting potential for novel therapies that target disposal of the mutant protein aggregates by harnessing a cellular homeostasis mechanism called autophagy. In this review, we will summarize research advances on autophagy and genetic liver diseases. We will discuss autophagy enhancer strategies for liver disease due to ATD and another genetic liver disease, inherited hypofibrinogenemia, caused by the proteotoxic effects of a misfolded protein. On the basis of recent evidence that autophagy plays a role in cellular lipid degradation, we also speculate about autophagy enhancer strategies for treatment of hepatic lipid storage diseases such as cholesterol ester storage disease.

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“…This is similar to alpha 1 AT deficiency and stimulation of autophagy by carbamazepine has been shown to help in clearing abnormal protein aggregates, prevent further deposition of abnormal protein and retard fibrosis progression. 65 …”

Section: Targeting Autophagy In Alfa-1 Antitrypsin Deficiencymentioning

confidence: 99%

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Puri

Chandra

2014

Journal of Clinical and Experimental Hepatology

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Autophagy is a critical intracellular pathway which maintains cellular function by lysosomal degradation of damaged proteins and organelles besides elimination of invading pathogens. Its primary function is to prevent cell death. Autophagy has diverse physiological functions namely; starvation adaptation, prevention of tumorigenesis, energy homeostasis, intracellular quality control and degradation of abnormal intracellular protein aggregates. Understanding the molecular mechanisms of autophagy has given key insights into the pathogenesis of various diseases like Non Alcoholic Steato-Hepatitis, Hepatitis B and C infections, Alpha-1 antitrypsin deficiency and hepatocellular carcinoma. Pharmacological modulation of autophagy may have a therapeutic potential in management of these liver diseases. ( J CLIN EXP HEPATOL 2014;4:51-59) O urobros or Urobros is an ancient symbol depicting a serpent or a dragon eating its own tail, which symbolizes cyclicality in the sense of something recreating itself. In living organisms, cells and intracellular organelles need to be constantly remodeled and renewed. Autophagy is a term derived from Greek terminology for self-eating and signifies the process of cellular selfdigestion in which cytoplasmic components are degraded in lysosomes. Reminiscent of the serpent eating its own tail in the symbol of Ourobros, the cells are able to survive by using autophagy to remove damaged proteins and organelles, eliminate invading microbes and generate nutrients during starvation.After Metchnicoff, a Russian zoologist, first described phagocytosis, the role of lysosomes and autophagy in degrading cytoplasmic components has been elucidated. 1,2 The control of autophagy has been recently delineated by identification of over 30 Autophagy-related (ATG) genes. 3 Autophagy functions to prevent rather than promote cell death. Autophagy has effects of increased cytoprotection, decreased stem cell attrition, decreased oncogenic transformation, decreased dysfunctional mitochondria and decrease in dysfunctional aggregate prone proteins. 4

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Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease

Cited by 50 publications

References 15 publications

Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy

Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy

Capitalizing on the Autophagic Response for Treatment of Liver Disease Caused by Alpha-1-Antitrypsin Deficiency and Other Genetic Diseases

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

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