![Measures of familiar lipids and lipid-containing nanostructures already inform healthcare. For example, high levels of low-density lipoprotein, low levels of high-density lipoprotein, and high levels of triglyceride are among the most common risk factors for heart disease and stroke. Yet comprehensive lipid surveys have been impractical, frustrating researchers interested in finding subtle (but important) connections between the lipidome and health. Fortunately, technologies such as liquid chromatography–mass spectrometry are beginning to expose the lipidome to close study. [JUAN GAERTNER / Science Photo Library / Getty Images]](https://www.genengnews.com/wp-content/uploads/2022/10/TL_Agilent-GettyImages-685022637-1-scaled.jpg "TL_Agilent-GettyImages-685022637")
The lipids in biological systems used to be seen as little more than energy reservoirs and insulating materials. Then they were found to serve additional functions. Lipids were identified as chemical messengers and as the main structural components of organelle and cell membranes.1 To perform all these functions, lipids occur in myriad forms. Indeed, lipids are so diverse that they defy comprehensive study—or they did, until the advent of lipidomics technologies such as liquid chromatography–mass spectrometry.
When lipidomics technologies are used to generate lipid profiles, it becomes easier to study how various lipids contribute to health. For example, these technologies can be used to detect excessively low or high levels of blood plasma lipids that contribute to some of the body’s most vital processes.2
In the blood, cholesterol commonly exists in two forms, free cholesterol and esterified cholesterol. Cholesterol may also occur in other forms, but these are not as well known. There are, however, some indications that some oxidized cholesterol lipids may be associated with abnormalities in metabolism. To learn more about alternative forms of cholesterol—and other lipid species that need closer scrutiny—researchers are applying mass spectrometry technology. [Dr_Microbe / iStock / Getty Images Plus]
Abnormal lipid levels may predict poor health outcomes. For example, high levels of “bad cholesterol,” low levels of “good cholesterol,” and high levels of triglyceride are among the most common risk factors for heart disease and stroke.3 Also, abnormal lipid levels are associated with obesity, which increases the risk of conditions such as high blood pressure and of diseases such as heart disease, diabetes, and cancer.4
Facing up to metabolism-related disorders
According to the U.S. Centers for Disease Control and Prevention, more than 37 million people in the United States have diabetes, making the disease the seventh leading cause of death in the country.5 In addition, one person dies every 34 seconds in the United States from cardiovascular disease,6 which costs the nation about $219 billion each year.7
To fight metabolism-related disorders, better clinical diagnostics and preventive interventions are needed. In late 2019, the National University of Singapore (NUS), the National University Hospital (NUH) in Singapore, and Agilent Technologies established the NUS-Agilent Hub for Translation and Capture (NUS-Agilent Hub). It consists of labs that leverage biochemical innovation and research data analytics to develop new methods of translating clinical research into clinical diagnostics.8 One of the labs is led by Markus R. Wenk, PhD, professor and head of biochemistry at NUS and director of the Singapore Lipidomics Incubator.
“[We aim] to understand the biological variations of metabolites,” Wenk says. “[These include] between-person variations across ethnicities and within-person changes over time.”
Launching collaborative research projects
The Wenk lab has been contributing to surveys of the circulatory lipidome. For example, as part of a multi-institutional collaboration, it analyzed 2,500 blood samples from participating mothers and their offspring in the Growing Up in
Singapore Towards healthy Outcomes (GUSTO) birth cohort study. (In this study, Wenk’s colleagues included Neerja Karnani, PhD, an adjunct associate professor of biochemistry at NUS and a senior principal investigator at A*STAR.)
After profiling 480 lipid species in mothers (during and after pregnancy) and their children (up to six years of age), the researchers presented the first developmental and intergenerational landscape of the human circulatory lipidome. The researchers also reported intergenerational similarities in circulatory lipids associated with obesity risk.9
This led to associations of certain metabolites with adiposity (severe or morbid obesity) that were not previously known. The most striking observation was that our circulatory lipidome—the fats, oils, waxes, etc., floating around in our bodily fluids—undergoes dramatic changes from birth to age six. At that time, it resembles that of an adult, that is, the mother.
The Wenk lab uses liquid chromatography–mass spectrometry to identify and quantify metabolites in small amounts of body fluids. The lab can also access advanced technologies such as high-speed sampling and inlet systems (to increase sample throughput) and leverage elemental spectrometry (to quantify atomic compositions).
Wenk notes that these technologies help his lab broaden its capabilities and “engage with clinical scientists and doctors.” The lab is positioned to join research efforts to better understand obesity, to map which metabolites (and perhaps foods) cause metabolic disorders, and to build models that help better predict and prevent these metabolism-related diseases.
Connecting the dots
At the Wenk lab, building connections between research labs and the wider world is a fundamental goal. He says that his lab is working to “connect the dots” for physicians, policymakers, and everyone who wants to tackle metabolism-related diseases.
For example, the Wenk lab recently joined a pilot project to integrate molecular phenotyping into a hospital’s routine operations. (The project’s participants include Kuan Win Sen, MRCS (A&E), an emergency physician and research director at NUH.) A primary focus is on patients who come to the emergency department with symptoms of inflammatory or vascular problems.
The care of such patients includes routine blood tests to assess organ function and clinical scores to stratify individuals according to the degree of complications. For patients who take part in the pilot program, an additional blood sample is taken and sent to Wenk’s lab, which obtains measurements for many of the molecules that independent studies have implicated as potential biomarkers for inflammation and vascular biology.
The researchers use their “emerging” tests—that is, their lab-developed tests—to generate predictive values. Then these values are compared with those generated by “established” tests. Of particular interest are tests to predict disease severity. If the emerging tests succeed, they will demonstrate the value of closely aligning translational research and clinical practice.
New tests to transform preventive medicine
Many large studies are using quantitative molecular measurements to assess individuals as they age, experience the onset of disease, and develop multiple morbidities. These studies reveal potential associations between physiological (or pathological) conditions and molecular markers.
According to Wenk, groups of molecular markers will be developed into panels for oxidative stress, frailty, or personal nutritional status. He says that molecular tests will be “very powerful new tools, particularly when combined with facile microsampling away from the hospital setting, in communities and home environments.” The tests could even be integrated with digital medicine technologies such as wearable technologies.
The Wenk lab is particularly interested in molecular markers that could inform preventive medicine. For example, the lab is collaborating with Mark Y. Chan, MBBS, an associate professor of medicine and deputy director of the Cardiovascular Disease Translational Research Program at NUS, to identify lipid markers of early onset coronary artery disease. During a six-month study of around 80 individuals facing subclinical coronary atherosclerosis, the Wenk lab collected blood samples monthly and noted the variability patterns over half a year for each individual and for the group as a whole.10
“One of the main findings … is that high person-specific longitudinal variation of lysophospholipids is associated with a worse plaque burden in individuals with subclinical coronary atherosclerosis,” Wenk reports. Research focusing on the pathophysiological effects of different lysophospholipids on atherosclerosis suggests that these lipid-derived signaling molecules may promote the pathogenesis of myocardial infarction and stroke.11
Living longer and healthier lives
Ultimately, the NUS-Agilent Hub’s lipidomics research will improve our understanding of metabolism-related disorders and inform the development of new diagnostic tests and preventive interventions that could benefit countless patients. For the Wenk lab and the NUS-Agilent Hub’s other labs, a key goal is the clinical implementation of new technologies to lower mortality and related statistics. The hope is that these technologies will help people with diabetes or cardiovascular disease live longer and healthier lives.
References
1. Tocher DR. Metabolism and functions of lipids and fatty acids in teleost fish. Rev. Fish. Sci. 2003; 11: 107–184. DOI: 10.1080/713610925.
2. Ahmed S, Shah P, Ahmed O. Biochemistry, Lipids. In: StatPearls. Treasure Island, FL. StatPearls Publishing; 2022. Accessed October 5, 2022.
3. Natesan V, Kim S-J. Lipid Metabolism, Disorders and Therapeutic Drugs—Review. Biomol. Ther. (Seoul) 2021; 29(6): 596–604. DOI: 10.4062/biomolther.2021.122.
4. Arslan N. Obesity, fatty liver disease and intestinal microbiota. World J. Gastroenterol. 2014; 20(44): 16452–16463. DOI: 10.3748/wjg.v20.i44.16452.
5. Centers for Disease Control and Prevention. Diabetes Fast Facts. Accessed October 5, 2022.
6. Centers for Disease Control and Prevention. Heart Disease Facts. Accessed October 5, 2022.
7. Centers for Disease Control and Prevention. Health Topics—Heart Disease and Heart Attack. Accessed October 5, 2022.
8. NUS, Agilent, and NUH launch new translational R&D hub to boost clinical diagnostics; 2019. Accessed October 5, 2022.
9. Mir SA, Chen L, Burugupalli S, et al. Developmental and Intergenerational Landscape of Human Circulatory Lipidome and Its Association with Obesity Risk. bioRxiv 2021. DOI: 10.1101/2021.04.23.437677.
10. Tan SH, Koh HWL, Chua JY, et al. Variability of the Plasma Lipidome and Subclinical Coronary Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2022; 42(1): 100–112. DOI: 10.1161/ATVBAHA.121.316847.
11. Li Y-F, Li R-S, Samuel SB, et al. Lysophospholipids and their G protein-coupled receptors in atherosclerosis. Front. Biosci. (Landmark Ed.) 2016; 21(1): 70–88. DOI: 10.2741/4377.
David Bradley is academia and collaborations manager, South Asia, Japan, and Korea, at Agilent Technologies.
