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Glycosyltransferase GLT25D2 Acts as a Negative Regulator of Autophagy to Promote Acetaminophen-Induced Hepatotoxicity
36 Pages Posted: 25 Oct 2018
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Glycosyltransferase GLT25D2 Acts as a Negative Regulator of Autophagy to Promote Acetaminophen-Induced Hepatotoxicity
Glycosyltransferase GLT25D2 Acts as a Negative Regulator of Autophagy to Promote Acetaminophen-Induced Hepatotoxicity
Abstract
Background: Acetaminophen (N-acetyl-para-aminophenol, APAP) overdose induces hepatocyte necrosis and causes liver injury. However, the role of galactosyltransferase in APAP-induced hepatotoxicity remains unclear. This study assessed the contribution of the collagen galactosyltransferase GLT25D2 gene to the development of APAP-induced liver injury.
Methods: GLT25D2 knockout, wild-type C57BL/6 mice and primary cultured hepatocytes were treated with APAP, and the related parameters of liver injury and autophagy were measured. Moreover, the serum and liver biopsy samples from drug-induced liver injury patients were further analyzed.
Results: The expression of GLT25D2 was markedly upregulated in the early stage of liver injury in mice treated with APAP, and knockout of GLT25D2 ameliorated the liver injury. Interestingly, knockout of GLT25D2 decreased the proinflammatory cytokines (TNF-α, IL-6) and chemokines (CXCL-1, CXCL-10 and MIG) levels, however, increased the anti-inflammatory cytokines (IL-10, IL-22) levels. Mechanistic investigations elucidated that (1) knockout of GLT25D2 enhanced autophagosome formation, promoted autophagy flux in vitro, but blocked autophagy flux in vivo; (2) the intervention of autophagy by Atg 7 knockdown abrogated liver protection by GLT25D2 knockout; and (3) the GLT25D2 knockout-induced autophagy selected to clear damaged mitochondria in APAP-induced hepatotoxicity by mitophagy. Moreover, the serum and livers levels of GLT25D2 was significantly downregulated in patients with drug-induced liver failure.
Conclusions: The upregulated GLT25D2 expression suppressed autophagy to contribute 3 / 26 to the development of APAP-induced hepatotoxicity.
Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (81770611, 81270532), the Natural Science Foundation of Beijing (7162085), Applied Research for the Clinical Characteristics of Capital (Z161100000516113), the High-level Technical Personnel Training Plan of the Beijing Health System (2013-3-075 and 2015-3-099), National Science and Technology Key Project on “Major Infectious Diseases such as HIV/AIDS, Viral Hepatitis Prevention and Treatment” (2018ZX10301407-005, 2018ZX10302205-004).
Declaration of Interests: "None"
Ethics Approval Statement: This study met the ethical guidelines of Declaration of Helsinki (1975), and the protocol was approved by the Medical Ethics Committee of Beijing YouAn Hospital.
Keywords: Acetaminophen, acute liver injury, autophagy, GLT25D2, glycosyltransferase
Suggested Citation: Suggested Citation