Hepatic Inactivation of the Type 2 Deiodinase Confers Resistance to Alcoholic Liver Steatosis

• Published in: Alcoholism, clinical and experimental research Vol. 43; no. 7; pp. 1376 - 1383
• Main Authors: Fonseca, Tatiana L., Fernandes, Gustavo W., Bocco, Barbara M. L. C., Keshavarzian, Ali, Jakate, Shriram, Donohue, Terrence M., Gereben, Balázs, Bianco, Antonio C.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.07.2019
• Subjects: ABCA1 protein; Alcohol use; Alcoholism; Alcoholism - complications; Alcoholism - genetics; Aldehyde dehydrogenase; Animals; Apolipoprotein E; ATP-binding protein; Binge Drinking; Deiodinase; Diet; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epigenetics; Ethanol; Ethanol - metabolism; Fatty Liver; Fatty Liver, Alcoholic - genetics; Fatty Liver, Alcoholic - metabolism; Fatty Liver, Alcoholic - prevention & control; Gene Expression Regulation; Gene regulation; Hypertriglyceridemia; Inactivation; Iodide peroxidase; Iodide Peroxidase - genetics; Iodide Peroxidase - metabolism; Iodothyronine Deiodinase Type II; Lipid Metabolism - genetics; Lipogenesis; Liver; Liver - metabolism; Low density lipoprotein receptors; Metabolic Networks and Pathways - genetics; Metabolic pathways; Mice; Mice, Knockout; Phenotypes; Secretion; Steatosis; Thyroid Hormone; Transcription; Triglycerides - metabolism; Deiodinase; Thyroid Hormone; Ethanol; Lipogenesis; Liver; Steatosis
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.14027

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. D2 activates T4 to T3. In the liver D2 is only detected during the first few days of life, where it enhances thyroid hormone signaling, affecting DNA methylation and the transcriptome. Here we show that inactivation of the D2 gene (Alb‐D2KO) renders mice resistant to alcoholic liver steatosis. This occurs in part via induction of the nuclear transcriptional repressor Zfp125 by ETOH feeding, which represses genes involved in VLDL secretion, defining susceptibility to alcoholic liver steatosis.