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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.zaEditorial