Medical Research Institute

Department of Biochemical Pathophysiology

Graduate School of Medical and Dental Sciences

Department of Lipid Biology

News＆ Topics

・ MRI Open Campus Day, 2020. 3/24（Tue）


Research


"Life science research focusing on lipids"

Molecules that shape organisms and support their activities can be roughly classified into three layers. From the top of the flow of information, they are genes, proteins, and metabolites. Metabolites are in a position that directly controls the states of an organism (phenotype). They fluctuate quantitatively and qualitatively in our bodies due to the effects of genes, proteins, diets, drugs, and symbiotic bacteria.

Lipids are the metabolites that are poorly soluble in water, and are used for compartmentalization of cells by membrane formation, energy storage, and signal transduction inside and outside cells. Research on lipids is yet to be advanced, as analytical methods have not been well-generalized compared to those for genes and proteins. That being the case, I believe that this is a research subject that will present new principles of life and provide a lot of knowledge to help overcome diseases. In fact, with the improvement of mass spectrometry technologies, the identification of new bioactive lipid molecules has recently been in succession. Our laboratory has also identified lipids with novel structure that fluctuate in cancers, neurological diseases, and inflammatory diseases. We are working on the identification of their synthesizing and degrading enzymes, physiological functions, and the molecular mechanisms of their actions.

"The four postulates to proceed with lipid research in the lab"

In conducting basic research in the lab to discover and present the relationship between lipids and diseases, we propose "four postulates of pathophysiological chemistry/lipid biology research," a lipid research version of Koch's postulates, as follows:

  1. Find a specific lipid that fluctuates in a certain human disease
  2. Identify the metabolic enzyme of the lipid
  3. Recapitulate the similar disease in laboratory animals by deleting/over-expressing the metabolic enzyme
  4. Find the same lipid change as in ① in that condition

There can be a variation that applies target proteins on which the lipid acts instead of metabolic enzymes.

Bearing in mind this basic strategy, we are working to elucidate the pathology of the following various diseases and devise medical applications based on this understanding.

・ Exploring novel phospholipids and their metabolic enzymes

・ Identifying phospholipids involved in cancer development and malignancy

・ Identifying phospholipids involved in basal ganglia neurodegeneration

・ Identifying phospholipids involved in pneumonia, colitis, and hepatitis

・ Studying regulatory mechanisms of target proteins (MD simulation, proteomics)

・ Stratification of lymphoma by lipid profiles

・ Prediction of the effects of molecular target drugs on cancers (breast cancer, pancreatic cancer, lymphoma, etc.) by lipid profiles






"Phosphoinositide metabolism in disease"

We have been pursuing a family of membrane phospholipids called phosphoinositides (PIPs) for over 20 years.

PIPs are the molecules that contain phosphatidylinositol, which has a glycerol backbone, two long-chain fatty acids, and an inositol head group. Combinatorial phosphorylation of the hydroxyls of the inositol gives rise to seven other PIPs classes. The differentially phosphorylated inositol headgroup of each PIPs class can interact with distinct sets of protein targets harboring one or more PIPs binding domains. In a cell, PIPs can activate those proteins by recruiting them to the membrane compartment where they act and by inducing their conformational changes, thereby regulate a wide variety of cellular responses such as cell growth, survival, metabolisms of glucose, proteins, lipids, and other biological processes. In mammals, the interconversion reactions involving all eight PIPs classes are mediated by as many as 50 genes encoding PIPs metabolizing enzymes (20 kinases and 30 phosphatases).

Our purpose is to achieve a comprehensive understanding of this whole metabolic system to propose new strategies for the treatment and diagnosis of incurable diseases. To this end, we have been generating and characterizing gene-targeted mouse mutants for each enzyme. Those mutant mice provide us with in vivo models to investigate the pathology of various types of cancer, inflammatory diseases, and neurodegenerative diseases. Another unique strength of our lab is the analytical methods for phospholipids. By developing mass spectrometry-based methods for PIPs measurement and applying it to human disease samples and pathological mouse models, we study the disease processes at the level of lipid molecules. Through these activities, we aim to deepen our understanding of the mechanism of biological regulation by lipids, present therapeutic targets for intractable diseases, and develop markers for predicting drug susceptibility and for disease stratification.


List of PIPs metabolizing enzymes

In the left figure showing the interconversion reaction, PIPs are placed at each vertex of the cube. The reactions by the kinases are represented by solid red lines and capital letters, and the reactions by the phosphatases are represented by dashed blue lines and small letters. In mammals, most reactions are redundantly controlled by multiple enzymes. The number of enzyme genes responsible for each reaction is shown on the right.

Phosphoinositide 3-kinase

Class/Type Protein Reactionb Gene symbol Chromosomal Locus Alternative names

Human Mouse

Class IA PI3K p110α K (A, E)c PIK3CA 3q26 3B PI3Kα/PIK3CA

p110β K (A, E) PIK3CB 3q22 9E4 PI3Kβ/PIK3CB

p110δ K (A, E) PIK3CD 1q36 4E2 PI3Kδ/PIK3CD

Class IB PI3K p110γ K (A, E) PIK3CG 7q22 12B PI3Kγ/PIK3CG

Class II PI3K PI3K-C2α A (E) PIK3C2A 11q15 7F1 PIK3C2α/Cpk-m

PI3K-C2β A (E) PIK3C2B 1q32 1E4 PIK3C2β

PI3K-C2γ A (E) PIK3C2G 12q12 6G2 PIK3C2γ

Class III PI3K Vps34 A PIK3C3 18q12 18B1 PIK3C3

Phosphatidylinositol 4-kinase

Class/Type Protein Reactionb Gene symbol Chromosomal Locus Alternative names

Human Mouse

Type II PI4K PI4KIIα B PI4K2A 10q24 19C3 PI4K2A

PI4KIIβ B PI4K2B 4q15 5C1 PI4K2B

Type III PI4K PI4KIIα B PIK4CA 22q11 16A3 PIK4CA/PI4KA

PI4KIIβ B PIK4CB 1q22 3F2.1 PIK4CB/PI4KB


注）Type I PI4Kは後の研究でPI3Kであることが見出された.

Phosphatidylinositol phosphate kinase

Class/Type Protein Reactionb Gene symbol Chromosomal Locus Alternative names

Human Mouse

Type I PIPK PIPKIα H PIP5K1A 1q22 19C1 PIP5KIα/PIP5K1A (mouse PIPKIβ/PIP5K1B)

PIPKIβ H PIP5K1B 9q13 3F2.1 PIP5KIβ/PIP5K1B (mouse PIPKIα/PIP5K1A)

PIPKIγ H PIP5K1C 19p13 10C1 PIP5KIγ/PIP5K1C

Type II PIPK PIPKIIα I PIP4K2A 10p12 2A3 PIP4K2A/PIP5K2A/PIP5KIIα

PIPKIIβ I PIP4K2B 17q12 11D PIP4K2B/PIP5K2B/PIP5KIIβ

PIPKIIγ I PIP4K2C 12q13 10D3 PIP4K2C/PIP5K2C/PIP5KIIγ

Type III PIPK PIPKIII F (C) PIP5K3 2p35 1C2 PIKfyve /p235/PIP5K3

Phosphoinositide 3-phosphatase

Class/Type Protein Reactionb Gene symbol Chromosomal Locus Alternative names

Human Mouse

PTEN PTEN e, k (a) PTEN 10q23 19C1 MMAC1/TEP1

Mytotubularin MTM1 a, g MTM1 Xq28 XA7.2 CNM/MTMX/XLMTM

MTMR1 a, g MTMR1 Xq28 XA7.2

MTMR2 a, g MTMR2 11q21 9A1 CMT4B/CMT4B1

MTMR3 a, g MTMR3 22q12 11A1 FYVE-DSP1/ZFYVE10

MTMR4 a, g MTMR4 17q22 11C FYVE-DSP2/ZFYVE11

MTMR6 a (g) MTMR6 13q12 14D1

MTMR7 a MTMR7 8p22 8B1.2

MTMR8 (a) MTMR8 Xq11 14D1 (mouse MTMR9)

MTMR14 a, g MTMR14 3p25 6E3 hJUMPY/hEDTP

Phosphoinositide 4-phosphatase

Class/Type Protein Reactionb Gene symbol Chromosomal Locus Alternative names

Human Mouse

INPP4 INPP4A d, (j) INPP4A 2q11 1B INPP4 type I

INPP4B d, (j) INPP4B 4q31 8C2 INPP4 type II

PIP4P PIP4P1 i PIP4P1 14q11 14C1 TMEM55B

PIP4P2 i PIP4P2 8q21 4A1 TMEM55A

Phosphoinositide 5-phosphatase

Class/Type Protein Reactionb Gene symbol Chromosomal Locus Alternative names

Human Mouse

Type II INPP5 SYNJ1 a ,b, f, h, i, j SYNJ1 21q22 16C3 synaptojanin 1/INPP5G/PARK20

SYNJ2 a ,b, f, h, i, j SYNJ2 6q25 17A1 synaptojanin 2/INPP5H

OCRL h, j OCRL Xq26 10D3 OCRL1/LOCR/Dent-2/INPP5F

INPP5B h, j INPP5B 1p34 4D2 5PTase/INPP5P

INPP5J h, j INPP5J 22q12 11A1 PIPP/PIB5PA

INPP5K j, (h) INPP5K 17p13 11B5 SKIP/PPS

Type III INPP5 SHIP1 j INPP5D 2q37 1D

SHIP2 j INPP5L1 11q13 7E2

Type IV INPP5 INPP5E f, h, j INPP5E 9q34 2A3 pharbin/MORMS/CPD4

Others

Class/Type Protein Reactionb Gene symbol Chromosomal Locus Alternative names

Human Mouse

Sac SAC1 a, b, (f) SACM1L 3q21 9F4

SAC2 h, j INPP5F 10q26 7F3

SAC3 f FIG4 6q21 10B1 CMT4J/ALS11

VSP VSP e, h, j TPTE2 13q12 8A2 TPIP/TPTE2 (mouse PTEN2)

PTPMT1 PTPMT1 c PTPMT1 11p113 2E1 PLIP