TY - JOUR
T1 - Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis
AU - Fonseca, Tatiana L.
AU - Fernandes, Gustavo W.
AU - Bocco, Barbara M.L.C.
AU - Keshavarzian, Ali
AU - Jakate, Shriram
AU - Donohue, Terrence M.
AU - Gereben, Balázs
AU - Bianco, Antonio C.
N1 - Publisher Copyright:
© 2019 by the Research Society on Alcoholism
PY - 2019/7
Y1 - 2019/7
N2 - Background: A mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of very-low-density lipoprotein. Methods: Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis. Results: The EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOH-induced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOH-containing diet for the same period of time. Their phenotype was associated with 1.3- to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6- to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH. Conclusions: EtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis.
AB - Background: A mouse with hepatocyte-specific deiodinase type II inactivation (Alb-D2KO) is resistant to diet-induced obesity, hepatic steatosis, and hypertriglyceridemia due to perinatal epigenetic modifications in the liver. This phenotype is linked to low levels of Zfp125, a hepatic transcriptional repressor that promotes liver steatosis by inhibiting genes involved in packaging and secretion of very-low-density lipoprotein. Methods: Here, we used chronic and binge ethanol (EtOH) in mice to cause liver steatosis. Results: The EtOH treatment causes a 2.3-fold increase in hepatic triglyceride content; Zfp125 levels were approximately 50% higher in these animals. In contrast, Alb-D2KO mice did not develop EtOH-induced liver steatosis. They also failed to elevate Zfp125 to the same levels, despite being on the EtOH-containing diet for the same period of time. Their phenotype was associated with 1.3- to 2.9-fold up-regulation of hepatic genes involved in lipid transport and export that are normally repressed by Zfp125, that is, Mttp, Abca1, Ldlr, Apoc1, Apoc3, Apoe, Apoh, and Azgp1. Furthermore, genes involved in the EtOH metabolic pathway, that is, Aldh2 and Acss2, were also 1.6- to 3.1-fold up-regulated in Alb-D2KO EtOH mice compared with control animals kept on EtOH. Conclusions: EtOH consumption elevates expression of Zfp125. Alb-D2KO animals, which have lower levels of Zfp125, are much less susceptible to EtOH-induced liver steatosis.
KW - Deiodinase
KW - Ethanol
KW - Lipogenesis
KW - Liver
KW - Steatosis
KW - Thyroid Hormone
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U2 - 10.1111/acer.14027
DO - 10.1111/acer.14027
M3 - Article
C2 - 30908637
AN - SCOPUS:85065029065
SN - 0145-6008
VL - 43
SP - 1376
EP - 1383
JO - Alcoholism: Clinical and Experimental Research
JF - Alcoholism: Clinical and Experimental Research
IS - 7
ER -