Takao Shimizu Discusses Lipid Mediators in Health and Disease
New Hot Paper Commentary, July 2010
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Article: Lipid Mediators in Health and Disease: Enzymes and Receptors as Therapeutic Targets for the Regulation of Immunity and Inflammation
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Takao Shimizu talks with ScienceWatch.com and answers a few questions about this month's New Hot Papers paper in the field of Pharmacology & Toxicology.
Why do you think your paper is highly
cited?
In addition to the well-known roles of lipids, they are also important as bioactive autacoids that regulate homeostasis, and lipid imbalances can cause bronchial asthma, rheumatoid arthritis, pulmonary fibrosis, and other diseases. Lipid mediators include prostaglandins, leukotrienes, lysophosphatidic acid, sphingosine 1-phosphate, and short-chain fatty acids, among others.
Each of these bioactive molecules is described individually in other review articles, but this paper gives, in a single chapter, complete and up-to-date information about the relevant structures, enzymes, receptors, and relations to diseases. I hope this paper gives readers an overview of the subject that is compact but still comprehensive, and helps them appreciate its complexity and importance.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
In the Supplementary Information, readers can find information about a novel method to simultaneously quantify multiple lipid mediators, which uses a lipidomics approach with LC/MS.
In addition, readers will understand that various lipid mediators are produced during the remodeling pathway of membrane phospholipids (which is called Lands' cycle). The description of the link between membrane remodeling (lipid biogenesis) and mediator production may also be new.
Would you summarize the significance of your paper
in layman's terms?
Lipids have long been thought of as having two roles: they are sources of energy and they are structural components of cell membranes. However, recent studies have shown that lipids also have a third role: they regulate many important bodily functions.
When the body needs bioactive lipids, it makes them using a series of enzymes. Then, the lipids have their effects by binding to specific receptors on the cell surface. If either those enzymes or the lipids' receptors (or both) do not function correctly, the result can be, for example, abnormal blood pressure, thrombosis, or problems with immune functions or with digestion.
We hope that understanding those processes will help us develop better treatments. For example, a "better aspirin" might be effective without causing gastric ulcers.
Figure 1:
Excess of bioactive lipids causes rheumatoid
arthritis.
View/download a pdf of three figures and descritions from Takao
Shimizu.
The paper also describes how structural lipids—those that make up cell membranes—are made and repaired when necessary. Surprisingly, these two very different roles of lipids (as structural components of cells and as regulators of body function) are tightly coupled to each other.
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you've encountered along the way?
After finishing my clinical training at the University of Tokyo Hospital, I received my Ph.D. at Kyoto University under the guidance of Prof. Osamu Hayaishi. I learned the enzymology and basic biochemistry of both tryptophan and prostaglandin metabolism.
I took my postdoctoral training at the Karolinska Institute under the supervision of Prof. Bengt Samuelsson (a Nobel laureate in Physiology and Medicine, 1982). Lipids are very difficult to handle, and no information is written from the genome sequence.
My experiences in Kyoto and in Stockholm showed me that lipids are quite challenging molecules to deal with. It was difficult in the beginning, because most lipid enzymes and receptors span membrane multiple times, and they are difficult to analyze biochemically.
The expression cloning of the PAF receptor using Xenopus oocytes (Nature 349: 342, 1991), which was actually the first successful cloning of lipid receptors (now more than 30 have been cloned), convinced me to devote my life to lipid research.
Because of lipids' insolubility in water and their instability by oxidation, some of the published results of lipid research have been unreliable (or just artifactual) and sometimes were retracted. I am quite lucky to have solid techniques for handling lipids and the knowledge of biochemistry that I gained during my doctoral and postdoctoral work.
Finally, I can't help noticing that many of the diseases caused by dysfunctions of lipid molecules (bronchial asthma, acute respiratory distress syndrome, abnormalities of alveolar surfactant, etc.) are the same conditions that I saw in patients 30 years ago almost every day, because my original clinical background was in respiratory medicine. I didn't expect it to be this way, but maybe I am like a salmon, instinctively returning to the river where I was born.
Where do you see your research leading in the
future?
I want to clarify the relationships among various inflammatory cytokines and lipid mediators, and find new small-molecule drugs to replace treatments that use antibodies. Lipid diversity and asymmetry (saturated vs. polyunsaturated fatty acids) may be related to membrane fusion, exocytosis, curvature, and fluidity.
We already have the tools we need to clarify the mechanism of diversity and its biological significance (tools such as cloning of many genes, knockout mouse, siRNA, etc.). To say it in words even stronger than those I used above, in the age of post-genomic medicine, lipid research is a medical biochemist's paradise. Gene databases give us no information; only biochemical analyses in combination with new biotechnology are useful.
Do you foresee any social or political
implications for your research?
Over the past 50 years, people in Japan and in other Asian countries started eating much more animal fat than before, and there have been increases in the incidence rates of diseases that were previously seen mainly in Western countries: colon cancer, atherosclerosis, Alzheimer's disease, diabetes mellitus, etc.
However, details of the links between the shift to a Western-style diet and the increased incidence of such diseases remain elusive (with the possible exception of our knowledge of the health effects of high cholesterol). With that in mind, it is clear that unbiased top-down lipidomics research should be seen as a top priority for public health.
I hope that the general public, national funding agencies, and
pharmaceutical companies will recognize the importance of lipid research.
Support for this work will contribute to disease prevention and to early
treatment, both of which will reduce the cost of medical care. I hope that
the work summarized in the paper and its references will benefit
society.
Takao Shimizu, M.D, Ph.D.
Dean
Professor
Department of Biochemistry and Molecular Biology
Faculty of Medicine
University of Tokyo
Tokyo, Japan
KEYWORDS: PHOSPHOLIPASE A2, PROSTAGLANDINS, LEUKOTRIENES, PLATELET-ACTIVATING FACTOR, GPCR, CYTOSOLIC PHOSPHOLIPASE A(2), PLATELET-ACTIVATING-FACTOR, PROTEIN-COUPLED RECEPTOR, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, COLLAGEN-INDUCED ARTHRITIS, INDUCED PULMONARY-FIBROSIS, LEUKOTRIENE B-4 RECEPTOR, EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS, LYSOPHOSPHATIDIC ACID RECEPTOR, APC(DELTA-716) KNOCKOUT MICE.