Ethnic differences in ectopic lipid deposition, fatty acid metabolism and the complement system between Black African-Caribbean and White European men

Abstract

Background: Obesity is one of the strongest risk factors for cardiometabolic disease and is hypothesised to drive ectopic lipid deposition and defective fatty acid metabolism, as well as complement dysregulation. However, these hypotheses are based on data from predominantly White Europeans (WE), and despite the high risk of type 2 diabetes (T2D) and ischaemic stroke in Black African-Caribbean (BAC) populations, little is known about ethnic differences in these pathophysiological pathways.

Aim: To investigate ethnic differences in ectopic lipid deposition between BAC and other ethnic groups, as well as comparing postprandial fatty acid metabolism and markers of the complement system, between WE and BAC men.

Methods: Ethnic differences in intrahepatic lipid (IHL), intramyocellular lipid (IMCL) and intrapancreatic lipid (IPL), between BAC and comparator ethnic populations, were investigated by systematic review and meta-analysis (where appropriate). In a postprandial study, ten WE and ten BAC men, who were overweight or obese, but otherwise healthy, were fed consecutive moderate-to-high fat meals. Stable isotope and density-gradient ultracentrifugation methodologies were utilised to investigate ethnic differences in the appearance of meal-derived fatty acids in plasma triacylglycerol (TAG), Svedberg floatation rate (Sf) > 400 TAG (approximating chylomicron-TAG) and Sf 20 – 400 TAG (approximating very low-density lipoprotein [VLDL]-TAG) and non-esterified fatty acids (NEFA), as well as their concentrations. Stable isotope methodology, alongside indirect calorimetry, was utilised to compare total and meal-derived fatty acid oxidation, and 3-hydroxybutyrate (3-OHB) was measured to compare hepatic ketogenesis. In-house enzyme-linked immunosorbent assays (ELISA) were utilised to compare ethnic differences in markers of the abundance and activation of the complement system, which included complement C3, Factor D, Ba, inactive C3b (iC3b) and terminal complement complex (TCC).

Results: There was strong evidence for lower IHL in BAC compared to other ethnic populations, which was supported by meta-analysis (p < 0.00001). There was also evidence for lower IPL in BAC, but IMCL appeared to be similar between BAC and WE. In the postprandial study, the BAC men exhibited lower postprandial TAG compared to WE (p = 0.022), which was driven by markedly lower Sf 20 – 400 TAG (VLDL-TAG; p = 0.003), and a trend for lower Sf > 400 TAG (chylomicron-TAG) in the late postprandial period (p = 0.057). BAC also exhibited significantly lower meal-derived fatty acids in Sf 20 – 400 TAG (p = 0.007), suggesting ethnic differences in meal-derived fatty acid metabolism. There were no significant ethnic differences in total or meal-derived NEFA, total or meal-derived fatty acid oxidation or 3-OHB following adjustment for NEFA concentrations. For markers of the complement system, there was a trend for lower postprandial Factor D (p = 0.097), and higher postprandial iC3b (p = 0.085) in BAC compared to WE. There were no significant ethnic differences in fasting or postprandial C3, Ba or TCC.

Conclusion: Lower fasting and postprandial plasma TAG in BAC, driven by lower Sf 20 – 400 TAG (VLDL-TAG) and Sf > 400 TAG (chylomicron-TAG) in the late postprandial period, are in line with lower IHL and IPL in BAC compared to WE. Similar IMCL is in line with similar fasting and postprandial NEFA between WE and BAC, but not lower TAG in BAC. Similar fatty acid oxidation and hepatic ketogenesis suggest that these fatty acid output pathways do not contribute to the observed ethnic differences in ectopic lipid deposition. The lower IHL, IPL and plasma TAG in BAC compared to WE are paradoxical to the high risk of T2D and ischaemic stroke experienced by this population. The investigation into ethnic differences in the complement system suggests that BAC may exhibit greater postprandial complement activation than WE, however this does not appear to be driven by ethnic differences in the activation of the alternative pathway; its relevance to the high risk of T2D and ischaemic stroke in BAC warrants further investigation. Collectively, these findings support the notion of ethnic differences in the pathophysiology of cardiometabolic disease in BAC populations.

Date of Award	1 Jul 2024
Original language	English
Awarding Institution	King's College London
Supervisor	Louise Goff (Supervisor) & Oliver Witard (Supervisor)