Characterising the effect of dietary fat composition on cardiac and hepatic function and metabolism

Thesis

Dietary macronutrient composition may modulate cardiometabolic disease (CMD) risk, as consuming a diet enriched in saturated fat (SFA), compared with unsaturated fat, leads to greater intrahepatic triglyceride (IHTG) accumulation, despite similar weight gain. However, it is difficult to differentiate the effects of weight gain from dietary fat composition on CMD risk as most studies have been conducted with overfeeding interventions. Therefore, the aim of this thesis was to investigate if, during weight-neutral conditions, dietary SFAs, compared with polyunsaturated FAs (PUFAs), undergo differential handling and induce divergent effects on hepatic and cardiac metabolism and function.

Participants free from diagnosed-metabolic disease consumed a mixed test meal with [U13C]palmitate or [U13C]linoleate after following a 3-day high-carbohydrate diet, which upregulated markers of hepatic de novo lipogenesis by ~65% (p<0.05). Despite shifting hepatic metabolism towards esterification and away from oxidation, appearance of 13C in expired CO2, a marker of whole-body dietary FA oxidation, was ~46% (p<0.01) greater following [U13C]linoleate compared with [U13C]palmitate consumption.

Participants free-from diagnosed metabolic disease underwent an MRI/S scan and postprandial study day with stable-isotope tracers before and after consuming an isocaloric SFA- or PUFA-enriched high-fat diet (HFD) for up to 24 days. There were minimal changes in body weight. However, consuming a PUFA-enriched HFD reduced IHTG content by ~19% (p<0.05) and induced beneficial changes in blood pressures, markers of whole-body dietary FA oxidation, cardiac PCr/ATP (pre: 1.52±0.13; post: 1.78±0.40; p<0.05), cardiac function, and insulin-kinetics. Consuming a SFA-enriched HFD tended to increase IHTG content BY ~17% (p=0.09), and adversely altered markers of cardiac function, whole-body dietary FA oxidation, and insulin resistance.

To further probe if FA composition, independent of FA quantity, impacts the heart, human inducible pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured in a 400µmol/L SFA- or PUFA-enriched FA mixture to model the human HFD from Chapter 4. PUFA-enriched lipid mix treated hiPSC-CMs did not reduce media FA uptake and upregulated FA metabolism pathways (padj<0.05), while SFA-enriched lipid mix treated hiPSC-CMs reduced FA uptake by ~67% (p<0.01) and upregulated ribosomal biogenesis (padj<0.05).

Taken together, these findings suggest dietary FAs undergo differential intracellular metabolism, dietary FA composition impacts CMD risk independent of body weight, and dietary FAs may directly modulate human cardiomyocyte metabolism and function.

Authors: Srnic, N

• DOI: 10.5287/ora-dabr5edq2
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: obesity; cardiovascular disease; dietary fat; human metabolism
• Subjects: Cardiology; Metabolism; Medicine