In this months’ science article, Kalliopi Dodou and Paul Whiteley take a look at the growing interest in the research of lipids
Lipids represent a catch-all term for a large number of compounds, including oils, fats and phospholipids, which collectively share the unifying trait of being hydrophobic. In their various guises they are abundant throughout the human body, constituting one of the major molecular schemes of biological function and life. For example, in the human brain, fat comprises about 60 per cent of the total matter volume. Such fats are linked to neuronal functions, including the insulating qualities of myelin. As Hirabayashi1 put it, there is “a world of sphingolipids and glycolipids in the brain”.
Steroids are important biological lipids. Steroids encompass the sex hormones, which play important roles in terms of gender, conception and contraception. They also encompass perhaps one of the most widely studied and discussed of the lipids, cholesterol, which has implications, both positive and negative, for various conditions and diseases that impact on health and well-being.
Outside neuronal and cardiovascular health, lipids also represent an essential part of cellular structure and functioning, providing a fuel source and playing a key role in important processes such as inflammation and immunity.
With the current focus on health indicators such as weight and the seemingly ever-growing link between waistline and risk of illness and early death, lipids have sometimes found themselves in the research and clinical spotlight for all the wrong reasons.
Not all fats are equal
Indeed, with such talk about lipids, or rather fats, and their excess consumption by people and storage in the body being linked to elevated rates of ill health and early mortality, it is easy to forget that not all fats are the same. Take, for example, the polyunsaturated fatty acids. These long hydrocarbon chains, with appropriately positioned double bonds, have become synonymous with animal and plant oil consumption, and there are several scientific debates on how we should all be eating more fish to potentially bring our omega-3/omega-6 fatty acid ratio back into evolutionary alignment.
Fish oils, particularly with the omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) for a wide range of conditions, ranging from heart health to cancer, ageing to cognitive disorders, is not universally efficacious. That is not, however, to say that maintaining a healthy diet inclusive of food groups high in omega-3 fatty acids might not be beneficial, particularly for specific groups of people.
In equal measure, one can also look to the rising tide of research being done on adipose tissue with its “brown fat=good fat and white fat=bad fat” mantra2 to understand that lipids are often unfairly portrayed as universally bad.
Lipidomics and the lipidome
Given the integral part that lipids play in human biochemistry, there is, unsurprisingly, a complete branch of science dedicated to the study of lipids. Based on the examination of the lipidome — the entire spectrum of lipids in a biological system3 — the science of lipidomics follows a similar path to other -omics. In some quarters, lipodomics is even thought of as a branch of metabolomics.4 The tools of analysis follow a well established theme: sample analysis by mass spectrometry or nuclear magnetic resonance coupled to the analytical and statistical prowess of a systems or computational biology approach to offer lipid profiles across various people, conditions and diseases. Accompanied by some interesting terms such as “shotgun lipidomics”5 — direct analysis of a sample without the need for chromatographic or electrophoretic separation first — there have been some surprising results reported in this relatively new field of endeavour.
The appliance of lipidomics
Various conditions have been visited by the research application of lipidomics, including cardiovascular, neurodegenerative and respiratory diseases.6 It is beyond the scope of this article to present them all, but a few potentially important areas will be discussed.
Diabetes and insulin sensitivity have received great attention. Kien and colleagues7 reported on a potentially important relationship between dietary fatty acid intake and measures of insulin sensitivity in young adults. They identified various medium-chain acylcarnitines as being negatively correlated to insulin sensitivity. Other work has similarly established a potential role for free fatty acids in arbitrating risk of insulin resistance and type 2 diabetes.
Zhao and colleagues8 used both lipidomics and transcriptomic (the study of gene expression patterns at the RNA level) analysis and concluded that, in combination, such analytical techniques revealed the emergence of enriched pathways that would not have been elucidated by genomic data alone.
As mentioned earlier, the sphingolipids and glycolipids are also beginning to be recognised as important lipids in health and disease. Sphingolipids, named after the Sphinx owing to their mysterious nature, are a particular type of lipid involved in important processes such as intracellular signal transmission.9
Apart from sphingolipidoses, a group of lipid storage disorders, several neurodegenerative conditions, including Alzheimer’s disease (AD), have been linked to sphingolipids10 and various other phospholipids.11
Indeed, the model put forward by Han and colleagues10 suggested that lower levels of sphingomyelin may affect lipid raft (membrane microdomains rich in sphingolipids) formation leading to other manifestations of AD, including plasma glucose accumulation. Whether or not this subsequently ties into the findings of elevated plasma Ab40 and Ab42 levels, classically associated with AD, as suggested by Takeda and colleagues,12 requires further study.
Cancer research is also an emerging field for the science of lipidomics. Work on lipid biomarkers for various cancers has been published on prostate13,14 and breast15 cancer.
The logic is based on the observations that lipid metabolism shows alteration during cancer16 and such alteration might provide an early warning system or even new avenues for drug development to affect tumour genesis and growth.
The relation between nutrition and lipidomics is a particularly interesting area of investigation. Understanding how what we eat, how we digest food and how we metabolise lipids can impact on health and well-being is gaining some research momentum,17 intersecting with other important biological systems, including the microbiome. Data are, for example, starting to emerge on characterising the role of plasma lipids in the metabolic syndrome18 and the complex relationships noted between lipids and inflammation and oxidative stress.
Chewing the fat
Lipidomics is a rising star in the -omics sciences. Technological advances, coupled to an increasing research interest in how lipids affect health and well-being, are coming together to further our knowledge in this area. Mapping of the human lipidome — reflecting the thousands of chemical species which have so far been identified — is an integral part of this process, which promises new insights and potentially new treatment options for a variety of illnesses and conditions.
1 Hirabayashi Y. A world of sphingolipids and glycolipids in the brain — novel functions of simple lipids modified with glucose. Proceedings of the Japan Academy — Series B: Physical and Biological Sciences 2012;88:129–43.
2 Collins F. Brown fat, white fat, good fat, bad fat. NIH directors blog. Available at: directorsblog.nih.gov/brown-fat-white-fat-good-fat-bad-fat/ (accessed 14 June 2013).
3 SeppÃ¤nen-Laakso T, Oresic M. How to study lipidomes. Journal of Molecular Endocrinology 2009;42:185–90.
4 Dodou K, Whiteley P. Metabolomics: in search of biomarkers. The Pharmaceutical Journal 2013;290:512.
5 Han X, Gross RW. Shotgun lipidomics: electrospray ionization mass spectrometric analysis and quantitation of cellular lipidomes directly from crude extracts of biological samples. Mass Spectrometry Reviews 2005;24:367–412.
6 Postle AD. Lipidomics. Current Opinion in Clinical Nutrition and Metabolic Care. 2012;15:127–33.
7 Kien CL, Bunn JY, Poynter ME et al. A lipidomics analysis of the relationship between dietary fatty acid composition and insulin sensitivity in young adults. Diabetes 2013;62:1054–63.
8 Zhao C, Mao J, Ai J et al. Integrated lipidomics and transcriptomic analysis of peripheral blood reveals significantly enriched pathways in type 2 diabetes mellitus. BMC Medical Genomics 2013;6 Suppl 1:S12.
9 Futerman AH, Hannun YA. The complex life of simple sphingolipids. EMBO Reprts 2004;5:777–82.
10 Han X, Rozen S, Boyle SH et al. Metabolomics in early Alzheimer’s disease: identification of altered plasma sphingolipidome using shotgun lipidomics. PLoS One 2011;6:e21643.
11 Wood PL. Lipidomics of Alzheimer’s disease: current status. Alzheimer’s Research and Therapy 2012;4:5.
12 Takeda S, Sato N, Uchio-Yamada K et al. Oral glucose loading modulates plasma beta-amyloid level in Alzheimer’s disease patients: potential diagnostic method for Alzheimer’s disease. Dementia and Geriatric Cognitive Disorders 2012;34:25–30.
13 Zhou X, Mao J, Ai J et al. Identification of plasma lipid biomarkers for prostate cancer by lipidomics and bioinformatics. PLoS One 2012;7:e48889.
14 Min HK, Lim S, Chung BC et al. Shotgun lipidomics for candidate biomarkers of urinary phospholipids in prostate cancer. Analytical and Bioanalytical Chemistry 2011;399:823–30.
15 Hilvo M, Denkert C, Lehtinen L et al. Novel theranostic opportunities offered by characterization of altered membrane lipid metabolism in breast cancer progression. Cancer Research 2011;71:3236–45.
16 Santos CR, Schulze A. Lipid metabolism in cancer. FEBS Journal 2012;279:2610–23.
17 HyÃ¶tylÃ¤inen T, Bondia-Pons I, OreÅ¡ic M. Lipidomics in nutrition and food research. Molecular Nutrition and Food Research. 15 February 2013. doi: 10.1002/ mnfr.201200759. [Epub ahead of print].
18 Meikle PJ, Christopher MJ. Lipidomics is providing new insight into the metabolic syndrome and its sequelae. Current Opinion in Lipidology 2011;22:210–15.