ABSTRACT
Ribosome biosynthesis is a major intracellular energy-consuming process. We previously identified a nucleolar factor, nucleomethylin (NML), which regulates intracellular energy consumption by limiting rRNA transcription. Here, we show that, in livers of obese mice, the recruitment of NML to rRNA gene loci is increased to repress rRNA transcription. To clarify the relationship between obesity and rRNA transcription, we generated NML-null (NML-KO) mice. NML-KO mice show elevated rRNA level, reduced ATP concentration, and reduced lipid accumulation in the liver. Furthermore, in high-fat-diet (HFD)-fed NML-KO mice, hepatic rRNA levels are not decreased. Both weight gain and fat accumulation in HFD-fed NML-KO mice are significantly lower than those in HFD-fed wild-type mice. These findings indicate that rRNA transcriptional activation promotes hepatic energy consumption, which alters hepatic lipid metabolism. Namely, hepatic rRNA transcriptional repression by HFD feeding is essential for energy storage.
Subject(s)
Diet, High-Fat , Liver/metabolism , RNA, Ribosomal/metabolism , Adenosine Triphosphate/metabolism , Animals , Energy Metabolism , Fatty Acids/biosynthesis , Gene Expression , Lipid Metabolism/genetics , Liver/diagnostic imaging , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Obese , Nuclear Proteins/deficiency , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Obesity/etiology , Obesity/metabolism , Obesity/pathology , RNA, Ribosomal/genetics , Sirtuin 1/metabolism , Tomography, X-Ray Computed , Transcription, GeneticABSTRACT
We previously identified a novel protein complex, eNoSC, which senses intracellular energy status and epigenetically regulates the rDNA locus by changing the ratio between the numbers of active and silent gene clusters. eNoSC contains a novel nucleolar protein, Nucleomethylin (NML), which has a methyltransferase-like domain and binds to Lys9-dimethylated histone H3 at the rDNA locus, along with the NAD(+)-dependent deacetylase SIRT1 and the histone methyltransferase SUV39H. The aim of this study was to determine the role of NML in liver after partial hepatectomy (PHx). We assessed liver regeneration and lipid metabolism after PHx in wild-type (WT) and NML transgenic (NML-TG) mice. Survival rates of NML-TG mice were reduced after PHx. We found that hepatic triglyceride content in NML-TG mice remained elevated 48h after PHx, but not delayed liver regeneration. Moreover, hepatic ATP levels in NML-TG mice were higher than that in WT 48h after PHx. These observations suggest that NML may regulate consumption of hepatic triglyceride in liver regeneration after PHx due to storage of excess ATP. The delayed consumption of hepatic triglyceride may be the cause of reduced survival rate in NML-TG mice.
