Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity

Abstract

Thyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase (D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of ∼165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10-20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.deiodinase | thyroid hormone | lipids | steatosis | obesity

The Foxo1-Inducible Transcriptional Repressor Zfp125 Causes Hepatic Steatosis and Hypercholesterolemia

“…The Zfp125 gene encodes an ~37-kDa C2H2-type zinc-finger protein (Figure 1A) identified as one of the top-ranking genes downregulated in liver of adult Alb-D2KO mice (Fonseca et al, 2015). Western blot studies indicate that liver is the site with highest Zfp125 expression (Figure 1A).…”

“…The Alb-D2KO mouse is resistant to diet-induced obesity and liver steatosis (Fonseca et al, 2015). Here, we identified the Foxo1-induciblegene Zfp125 as key mediator of this phenotype.…”

“…Elimination of the perinatal surge in hepatocyte D2 affects, later in life, liver expression of ~165 genes involved in lipid metabolism (Fonseca et al, 2015). Between 10% and 20% of these genes exhibit differentially methylated regions (DMRs) and thus qualify as epigenetic modifications caused by Dio2 inactivation.…”

“…Interest in this pathway was reawakened recently with the observation that D2 is expressed transiently in the neonatal mouse liver: hepatic D2 expression and enzyme activity peaks on post-natal day 1 (P1) and is rapidly silenced by P5 down to background levels. This brief peak of D2-generated T3 modifies the methylation pattern and the expression levels of thousands of hepatic genes, increasing future susceptibility to diet-induced obesity and liver steatosis (Fonseca et al, 2015). …”

“…Adult Alb-D2KO animals are less susceptible to liver steatosis, hypertriglyceridemia, and obesity when placed on a high-fat diet (HFD). A microarray study identified 165 genes that are differentially expressed in the adult Alb-D2KO liver, 10%−20% of which contain differential DNA methylation (Fonseca et al, 2015). Among the most differentially expressed genes in the liver of Alb-D2KO mice is the Cys2Hys2 (C2H2) zinc-finger protein 125 (Zfp125), previously associated with muscle cell proliferation and transformation (Giorgi et al, 1999).…”