CD36 Modulates Fasting and Preabsorptive Hormone and Bile Acid Levels

Abstract

Context: Abnormal fatty acid (FA) metabolism contributes to diabetes and cardiovascular disease. The FA receptor CD36 has been linked to risk of metabolic syndrome. In rodents CD36 regulates various aspects of fat metabolism, but whether it has similar actions in humans is unknown. We examined the impact of a coding single-nucleotide polymorphism in CD36 on postprandial hormone and bile acid (BA) responses.

Objective: To examine whether the minor allele (G) of coding CD36 variant rs3211938 (G/T), which reduces CD36 level by ∼50%, influences hormonal responses to a high-fat meal (HFM).

Design: Obese African American (AA) women carriers of the G allele of rs3211938 (G/T) and weight-matched noncarriers (T/T) were studied before and after a HFM.

Setting: Two-center study.

Participants: Obese AA women.

Intervention: HFM.

Main outcome measures: Early preabsorptive responses (10 minutes) and extended excursions in plasma hormones [C-peptide, insulin, incretins, ghrelin fibroblast growth factor (FGF)19, FGF21], BAs, and serum lipoproteins (chylomicrons, very-low-density lipoprotein) were determined.

Results: At fasting, G-allele carriers had significantly reduced cholesterol and glycodeoxycholic acid and consistent but nonsignificant reductions of serum lipoproteins. Levels of GLP-1 and pancreatic polypeptide (PP) were reduced 60% to 70% and those of total BAs were 1.8-fold higher. After the meal, G-allele carriers displayed attenuated early (-10 to 10 minute) responses in insulin, C-peptide, GLP-1, gastric inhibitory peptide, and PP. BAs exhibited divergent trends in G allele carriers vs noncarriers concomitant with differential FGF19 responses.

Conclusions: CD36 plays an important role in the preabsorptive hormone and BA responses that coordinate brain and gut regulation of energy metabolism.

Trial registration: ClinicalTrials.gov NCT02126735.

Figures

Figure 1.

Serum nutrient and lipoprotein responses to high-fat feeding in individuals carrying the G allele of rs3211938 (G/T) and control (T/T) noncarriers. (A) Serum TGs, (B) FFAs, (C) total VLDL and chylomicrons, and (D) medium VLDL particle concentrations in carriers compared with noncarriers are shown. (E) Serum phospholipid and (F) cholesterol concentrations at baseline and 240 minutes after an HFM are shown. Values shown as means ± SEM (n = 11 for T/T and n = 9 for G/T). *P ≤ 0.05 by unpaired, two-tailed Student t test.

Figure 2.

CD36 insufficiency alters the hormonal responses to an HFM. Plasma levels at −10 to 360 minutes after the meal of (A) C-peptide, (B) insulin, (C) PP, (D) GLP-1, (E) GIP, and (F) acyl-ghrelin in G-allele and T-allele carriers are shown. Early preabsorptive changes −10 to 10 minutes after the meal in levels of (G) C-peptide, (H) insulin , (I) PP, (J) GLP-1, (K) GIP, and (L) ghrelin are shown. Data are means ± SEM (n = 9 for G/T and n = 11 for T/T). *P ≤ 0.05, **P ≤ 0.01.

Figure 3.

CD36 insufficiency alters fasting and HFM-stimulated BA levels and fasting levels of FGF19. (A) Plasma total BAs from −10 to 360 minutes after the HFM. Early changes (from −10 to 10 minutes) of (B) total BAs, (C) conjugated BAs, and (D) GDCA are shown. (E) Excursion curves of total BAs from −10 to 360 minutes after HFM. Early changes in (F) 12α-hydroxylated BAs and (G) 12α-hydroxylated/non–12α-hydroxylated ratio are shown. (H and I) Levels of FGF19 (H) and FGF21 (I) at 0 and 120 minutes after the HFM. n = 8 for G/T and n = 11 for T/T. *P ≤ 0.05, ***P ≤ 0.001, ****P ≤ 0.0001 by unpaired, two-tailed Student t test.