Association of hemoglobin A1C with circulating metabolites in Dutch with European, African Surinamese and Ghanaian background.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) varies significantly across ethnic groups. A better understanding of the mechanisms underlying the variation in different ethnic groups may help to elucidate the pathophysiology of T2DM. The present work aims to generate a hypothesis regarding "why do subjects with African background have excess burden of T2DM?". METHODS: In the current study, we performed metabolite profiling of plasma samples derived from 773 subjects of three ethnic groups (Dutch with European, Ghanaian and African Surinamese background). We performed Bayesian lognormal regression analyses to assess associations between HbA1c and circulating metabolites. RESULTS: Here we show that subjects with African Surinamese and Ghanaian background had similar associations of HbA1c with circulating amino acids and triglyceride-rich lipoproteins as subjects with European background. In contrast, subjects with Ghanaian and African Surinamese background had different associations of HbA1c with acetoacetate, small LDL particle and small HDL particle concentrations, compared to the subjects with European background. CONCLUSIONS: On the basis of the observations, we hypothesize that the excess burden of T2DM in subjects with African background may be due to impaired cholesterol efflux capacity or abnormal cholesterol uptake.

Transgenic overexpression of Niemann-Pick C2 protein promotes cholesterol gallstone formation in mice.

BACKGROUND & AIMS: Niemann-Pick C2 (NPC2) is a lysosomal protein involved in the egress of low-density lipoprotein-derived cholesterol from lysosomes to other intracellular compartments. NPC2 has been detected in several tissues and is also secreted from the liver into bile. We have previously shown that NPC2-deficient mice fed a lithogenic diet showed reduced biliary cholesterol secretion as well as cholesterol crystal and gallstone formation. This study aimed to investigate the consequences of NPC2 hepatic overexpression on liver cholesterol metabolism, biliary lipid secretion, gallstone formation and the effect of NPC2 on cholesterol crystallization in model bile. METHODS: We generated NPC2 transgenic mice (Npc2.Tg) and fed them either chow or lithogenic diets. We studied liver cholesterol metabolism, biliary lipid secretion, bile acid composition and gallstone formation. We performed cholesterol crystallization studies in model bile using a recombinant NPC2 protein. RESULTS: No differences were observed in biliary cholesterol content or secretion between wild-type and Npc2.Tg mice fed the chow or lithogenic diets. Interestingly, Npc2.Tg mice showed an increased susceptibility to the lithogenic diet, developing more cholesterol gallstones at early times, but did not show differences in the bile acid hydrophobicity and gallbladder cholesterol saturation indices compared to wild-type mice. Finally, recombinant NPC2 decreased nucleation time in model bile. CONCLUSIONS: These results suggest that NPC2 promotes cholesterol gallstone formation by decreasing the cholesterol nucleation time, indicating a pro-nucleating function of NPC2 in bile.

Effect of cholecystectomy on bile acid synthesis and circulating levels of fibroblast growth factor 19.

UNLABELLED: Background and rationale for the study. FGF19/15 is a gut-derived hormone presumably governing bile acid (BA) synthesis and gallbladder (GB) refilling. FGF19 mRNA is present in human GB cholangiocytes (hGBECs); however, the physiological significance of GB-derived FGF19 remains unknown. We investigated whether hGBECs secrete FGF19 and the effects of cholecystectomy on serum FGF19 ([FGF19]s) and BA synthesis. MATERIAL AND METHODS: FGF19 expression was assessed by qRT-PCRs and immunostaining in hGBECs and terminal ileum, and quantified in bile and serum by ELISA. Basal and BA (chenodexycholic acid, CDCA) induced FGF19 expression and secretion was analyzed in primary cultured hGBECs and GB-d1 cell line. Pre and postprandial serum changes in [FGF19]s, 7α-hydroxy-4-cholestene-3-one (C4, a marker of BA synthesis) and BA were evaluated in plasma of gallstone disease patients at baseline and after cholecystectomy. RESULTS: FGF19 mRNA levels were ~250-fold higher in hGBECs compared to distal ileum. GB bile contained ~23-fold higher FGF19 levels compared to serum (p < 0.0001). CDCA induced dose-dependent expression and secretion of FGF19 in hGBECs and GB-d1 cells. Cholecystectomy increased plasma BA synthesis ≥ 2-fold (p < 0.0001), and altered the diurnal rhythm and significantly reduced [FGF19]s noon peak. BA serum levels, serum cholesterol and triglyceride content remained unchanged. CONCLUSIONS: In conclusion human GB cholangiocytes constitutively express and secrete high levels of FGF19 in a process regulated by BA. Resection of this organ doubles BA synthesis concomitantly with changes in [FGF19]s. These findings suggest a potential connection between GB cholangiocytes-derived FGF19 and BA metabolism that could lead to metabolic dysregulation following cholecystectomy.