CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 4, July/August 2019 AFRICA 191 Searching the lipidome for answers to prevent and treat non-communicable diseases Louise van den Berg, Corinna Walsh Non-communicable diseases (NCDs), once restricted to certain affluent societies, currently represent 70% of all global mortality, and are predicted to be the leading cause of morbidity and mortality in all regions of the world by 2030. 1 Cardiovascular diseases (CVD) and diabetes count among the four NCDs that cause over 80% of all premature deaths. Finding effective ways to predict, prevent and treat these diseases is, therefore, essential to address this growing threat to global health and economic security. 1,2 The significant drivers for NCDs, particularly CVD and diabetes, are modifiable behavioural risk factors, including unhealthy diets and physical inactivity, which cause a specific clustering of metabolic abnormalities referred to as the metabolic syndrome (MetS). The severity of these metabolic abnormalities predicts the risk for and progression to the associated NCDs. 3 The MetS is defined as the presence of at least three out of five clinical risk factors, namely abdominal obesity (defined by waist circumference above population-specific thresholds), hypertension, insulin resistance, elevated serum triglycerides and low serum high-density lipoprotein cholesterol. 4,5 Obesity, however, is not a homogeneous condition across individuals. The MetS and associated metabolic abnormalities occur in some apparently healthy and lean individuals. 6 Moreover, 25–40% of obese individuals do not present with metabolic abnormalities associated with the MetS, 7 although recent studies do suggest that metabolically healthy obesity (HO) is transient and, over time, does transform to the MetS. 8,9 Simple anthropometric screening, therefore, does not always reflect the biological effects of excessive body fat on health. Additional molecular characterisations of lean and obese phenotypes are needed to assess the risk of developing subsequent metabolic conditions at the individual level. One area of study for finding predictive biomarkers is the lipidome, including the adipose tissue, circulating free fatty acids, and the phospholipid bilayers that constitute cellular and sub-cellular membranes. Adipose tissue, far from just a caloric reservoir, is metabolically active. In the obese state, the enlarged adipose tissue is transformed by macrophage infiltration and enhanced inflammatory activity, causing increased levels of circulating pro-inflammatory cytokines. These cytokines include tumour necrosis factor-alpha and interleukin-6, which are associated with insulin resistance 10 and increased risk for CVD and type 2 diabetes mellitus (T2DM). 10-12 The serum/plasma free fatty acid profile, in turn, reflects fatty acid metabolism and dietary intake, providing an objective assessment of dietary fat composition that is potentially independent of the errors associated with reliance on self-reported dietary intake. Obese individuals present with chronically elevated circulating free fatty acid levels, which may, therefore, serve as a biomarker of obesity-associated MetS and CVD. 13 Increased risk for NCDs has been associated with higher levels of circulating and phospholipid bilayer-associated saturated fatty acids (SFAs); studies indicate that increasing membrane rigidity may be one plausible mechanism by which SFA levels are associated with the risk for T2DM and CVD. 14 Conversely, long-chain mono-unsaturated fatty acids (LCMUFAs) and long- chain poly-unsaturated fatty acids (LCPUFAs) contribute to the fluidity of the phospholipid bilayers, which could explain at least some of the protective effects against NCDs reported in many studies. Beyond membrane fluidity, n-6 and n-3 LCPUFAs in the phospholipid bilayers serve as substrates for several enzymes that produce pro- and anti-inflammatory oxylipins, rendering them potent modulators of cytokine production. 15 The distinction between HO and the MetS was recently proposed to be related to the degree of chronic inflammation present. 16 An increase in plasma and phospholipid bilayer- associated n-6 results in a decrease of n-3 LCPUFAs in the plasma and phospholipid bilayers, and higher concentrations of plasma n-6 oxylipins; 17 therefore, an increased n-6/n-3 ratio is associated with increased inflammation in obesity. 18 A recent meta-analysis of 21 studies 15 found that the composition of LCPUFAs in the circulation and phospholipid bilayers differed significantly between overweight and obese compared to normal-weight subjects. Obese subjects had significantly lower n-6 linolenic acid (LA) levels and significantly higher levels of dihomo-γ-linolenic acid (DGLA), compared with controls in all the investigated biomarkers. The meta- analysis also found that the activity of Δ6-desaturase, which converts GLA (which in turn, is derived from LA in the phospholipid bilayers) to DGLA, was significantly increased in the overweight and obese subjects. Conversely, the activity of Δ5-desaturase, which converts DGLA to arachidonic acid (AA), was significantly decreased in the overweight and obese subjects. 15 Overall, this accounts for the accumulation of DGLA, which is a crucial player in the synthetic pathway for pro-inflammatory oxylipins; therefore elevated levels of this LCPUFA may Department of Nutrition and Dietetics, University of the Free State, South Africa Louise van den Berg, BMedSc, BMedSc Hons (Haematology), MSc (Immunology), PhD (Immunology), BSc Dietetics Corinna Walsh, BSc Dietetics, MSc (Dietetics), PhD (Nutrition), WalshCM@ufs.ac.za Editorial