Research project 1
Fatty acid elongase Elovl6 and its role in energy homeostasis and metabolic diseases
– Development of new strategy for the treatment of lifestyle-related diseases by qualitative control of fatty acids –
The prevalence of obesity and metabolic disease has grown to epidemic proportions. Therefore, understanding of the molecular basis of energy metabolism and development of the effective therapeutic approaches for preventing lifestyle-related diseases are called for immediately. We are working to understand the molecular mechanisms of which the nutrient signals lead to fatty acid synthesis. In this process, we identified and characterized a novel mammalian fatty acid elongase, Elovl6, which catalyzes the elongation of saturated and monounsaturated fatty acids with 12, 14, and 16 carbons (J Lipid Res. 43:911, 2002). We have also shown that mice with targeted disruption of Elovl6 are resistant to diet-induced insulin resistance, despite their developing obesity (Nat Med. 13:1193, 2007). These results suggest that inhibition of this elongase could be a new therapeutic approach for the treatment of diabetes, cardiovascular disease and other metabolic diseases, even with concurrent obesity.
In this research project, we try to elucidate the molecular mechanism of the regulation of energy homeostasis and cellular functions by the change in fatty acid composition through analyses of Elovl6. We also try to extend our investigations to develop new therapeutic approaches for treating lifestyle-related disease based on control of fatty acid composition.
Research project 2
Unraveling and therapeutic exploitation of a novel metabolic system orchestrated by an energy metabolite sensor
We are currently focusing on a transcriptional cofactor that serves as an energy metabolite sensor.
Historically, substrates and end-products of metabolic enzymatic reactions have been under intensive investigation without particular emphasis on the metabolic intermediates. However, it has been gradually revealed that those metabolic intermediates play multifaceted roles in a wide variety of biological systems including epigenetic regulation, enzymatic reactions and transcriptional regulation, linking these metabolites to pathogenesis of not only metabolic disorders but also broader range of diseases such as cancer, auto-immune diseases, osteoarthropathy and cardiovascular diseases.
We identified a critical molecule that integrates those metabolic intermediates to orchestrate metabolic homeostasis. Metabolic reactions of nucleotides and fatty acids yield metabolic intermediates that alters the activity of the molecule, contributing to homeostatic regulation of our biological systems. We have already initiated to discover novel small molecule(s) targeting the metabolite sensor to treat metabolic disorders as well as other diseases.
We recently obtained multiple options to treat metabolic disorders. However, we are still facing numerous patients untreatable with those medications. We are attempting to understand the complex web of metabolic systems by targeting the metabolite sensor molecule to overcome our current limitations and discover next-generation medicines.
Research project 3
Elucidation of transcription factor network regulating gene expression of enzymes involved in metabolic syndrome
Metabolic syndrome is the main of health problems in modern society. When the deterioration of disease condition worsens, it progresses to a state that leads to death such as cardiovascular disease and cancer. There is abnormality in nutritional metabolism at the beginning of the lifestyle disease. It is necessary to elucidate the abnormality at the molecular level to construct new therapeutic strategy for metabolic syndrome. The breakdown of the balance between absorption and consumption of nutrition promotes overnutrition accumulation in the body, causing obesity. Therefore, it is necessary to consider pathology from nutrient absorption from the small intestine, nutritional metabolism in the liver, and nutrient accumulation in the peripheral tissues including adipose tissue. From this point of view, we focus on transcription factors that regulate gene expression. Among many transcription factors controlling the expression of genes involved in nutritional metabolism, especially, Cyclic AMP Response Element-binding Protein H (CREBH) functioning to improve lipid metabolism and Sterol regulatory element-binding protein (SREBP) to exacerbate it. We analyze nutritional metabolic regulation by crosstalk between transcription factors
Function of the transcription factor CREBH in the enterohepatic circulation and metabolic syndrome
We have analyzed the function of membrane-bound transcription factors (CREBH, SREBP) localizing in the endoplasmic reticulum. SREBP is expressed in tissues of the whole body, whereas CREBH is expressed only in the small intestine which is the nutrient absorbing tissue at the root of nutritional metabolism and the liver which is a nutritional metabolism tissue.
CREBH directly increases expression of lifestyle-related disease improving hormone Fibroblast Growth Factor 21 (FGF 21) in the liver and suppresses diet-induced obesity (Nakagawa et al., 2014). CREBH improves lipid metabolism by controlling the expression of the transcription factor PPARα which is also a nuclear receptor that improves lipid metabolism. Furthermore, we found that CREBH and PPARα form the auto-loop activation mechanism that controls mutual expression, resulting in the effective improvement of lipid metabolism (Nakagawa et al., 2014) (Nakagawa et al., 2016b) (Nakagawa and Shimano, 2018).
In CREBH deficient mice, diet-induced nonalcoholic fatty liver deteriorates earlier and quickly causes hepatitis (Nakagawa et al., 2016a). However, the detailed analysis is necessary for its molecular mechanism.
CREBH in the small intestine lowers blood cholesterol by suppressing the expression of cholesterol absorption transporter NPC1L1 in the small intestine. Therefore, small intestinal CREBH overexpressing mice suppress gallstone formation induced by high cholesterol diet (Kikuchi et al., 2016).
We created tissue-specific CREBH-deficient mice independently created using the CRISPR / Cas9 system (Nakagawa et al., 2016 a). It was the first time in the world that a tissue specific knockout mouse was created and analyzed after inserting the Lox P sequence into the genome at two sites by DNA injection into one fertilized egg.
Now, we are trying to elucidate the mechanism of CREBH functioning in the liver, small intestine, the linkage of two tissues (enterohepatic circulation) to the nutritional metabolism, and the influence on CREBH on other peripheral tissues. Then, we are analyzing the molecular level in pathogenesis such as nonalcoholic fatty liver and arteriosclerosis.
Kikuchi, T., Orihara, K., Oikawa, F., et al. (2016). Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression. Mol Metab 5, 1092-1102.
Nakagawa, Y., Oikawa, F., Mizuno, S., et al. (2016a). Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system. Sci Rep 6, 27857.
Nakagawa, Y., Satoh, A., Tezuka, H., et al. (2016b). CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARalpha. Sci Rep 6, 39182.
Nakagawa, Y., Satoh, A., Yabe, S., et al. (2014). Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes. Endocrinology 155, 4706-4719.
Nakagawa, Y., and Shimano, H. (2018). CREBH Regulates Systemic Glucose and Lipid Metabolism. Int J Mol Sci 19.
Molecular mechanism of lifestyle-related disease onset due to sleep abnormality
Sleep anomalies are said to cause lifestyle-related diseases, but they have not been demonstrated at the molecular level. Therefore, we examine how sleeping abnormal mice develop lifestyle-related diseases.
Research project 4
Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba
We have established a quantitative system (in vivo Ad-luc analysis method) combining introduction of luciferase reporter gene by adenovirus to liver and biological imaging (IVIS) as an assay system using individuals for analysis of nutritional signals.
Moreover, we have independently developed an expression library (TFEL: Transcription Factor Expression Library) covering all transcription factors on the genome and established transcription complex analysis method (TFEL scan method) using it.
By utilizing in vivo Ad-luc analysis method and genome editing technology, we are proceeding with the identification of the region on the genome where various nutrient signals are projected, and by combining our unique TFEL scan transcription complex analysis method, We will aim to elucidate the interaction between nutrient signal and genome.
For further details of the research, please refer to the website of the University of Tsukuba Medical and Nutrigenomics Research Group (https://nyahagi.wixsite.com/ngrg).
Research project 5
Visualization and manipulation technology of metabolic responsive transomics network
Cells dynamically change information of different hierarchies such as transcriptome, proteome, and metabolome in the process of sensing and processing information on the surrounding environment. At this time, the omics information of each hierarchy is not independent, it is coded as a “transomics network” closely interlocking, and the cell selects and executes an appropriate function according to the situation based on the coded information It is thought that it is. Among these omics information, metabolome information is the result of summarizing the results of omics information of other hierarchies, and at the same time it is important that we have great influence on omics information of other hierarchies and intracellular signal dynamics constructed by them It is reported by.
Our group defines an information network composed of processes in which a change in certain metabolic information results in a specific output as a “metabolically responsive transomics network”, and a reputational approach (such as the omics analysis and information dynamics Visualization) and a constructive approach (development of Programmable Biocomputing Devices), we are trying to elucidate the whole of it.
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- Miyamoto T, Lo PHY, Saichi N, Ueda K, Hirata M, Tanikawa C, Matsuda K. Argininosuccinate synthase 1 is an intrinsic Akt repressor transactivated by p53. Sci Adv. 2017:e1603204.
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