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Neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) work closely with leptin and insulin to fine-tune the metabolic and neuroendocrine responses to dietary intake. Losing the sensitivity to excess food intake can lead to obesity, diabetes, and a multitude of behavioral disorders. It is largely unclear how different serotonin receptor subtypes respond to and integrate metabolic signals and which genetic variations in these receptor genes lead to individual differences in susceptibility to metabolic disorders. In an obese cohort of families of Northern European descent (n = 2,209), the serotonin type 5A receptor gene, HTR5A, was identified as a prominent factor affecting plasma levels of triglycerides (TG), supported by our data from both genome-wide linkage and targeted association analyses using 28 publicly available and 12 newly discovered single nucleotide polymorphisms (SNPs), of which 3 were strongly associated with plasma TG levels (P < 0.00125). Bayesian quantitative trait nucleotide (BQTN) analysis identified a putative causal promoter SNP (rs3734967) with substantial posterior probability (P = 0.59). Functional analysis of rs3734967 by electrophoretic mobility shift assay (EMSA) showed distinct binding patterns of the two alleles of this SNP with nuclear proteins from glioma cell lines. In conclusion, sequence variants in HTR5A are strongly associated with high plasma levels of TG in a Northern European population, suggesting a novel role of the serotonin receptor system in humans. This suggests a potential brain-specific regulation of plasma TG levels, possibly by alteration of the expression of HTR5A.

Turnover rates of plasma very low density lipoprotein (VLDL) triglyceride (TG) and apolipoprotein-B (apo-B) were significantly increased in age- and weight-matched groups of normolipemic and hyperlipemic mild diabetics, and hyperlipemic moderately severe diabetics when compared with normolipemic controls. As in the normolipemic subjects, a significant correlation between VLDL TG and apo-B turnover rates was found in all diabetic groups, suggesting that integration of TG and apo-B production at synthetic and/or secretory sites is retained in diabetes, thus resulting in increased secretion of VLDL particles of normal composition. In normolipemic mild diabetic subjects, the fractional turnover rates of VLDL TG and apo-B were also significantly increased so that increased removal accompanied increased VLDL production. In the hyperlipemic diabetics, however, the fractional turnover rates were significantly reduced, hence the increased in VLDL removal was not sufficient to compensate for enhanced production. In normolipemic mild diabetic patients, low density lipoprotein (LDL) formation was increased, only a small fraction of VLDL apo-B being removed via a non-LDL pathway, presumably as remnant VLDL. In hyperlipemic mild diabetics, removal of VLDL apo-B via both the LDL and non-LDL pathways was increased. In hyperlipemic moderately severe diabetes, LDL formation was not increased; catabolism of VLDL apo-B through the non-LDL route was however, fivefold greater than normal. We conclude that increased VLDL secretion is a fundamental defect in non-insulin-dependent diabetes. In hyperlipemic individuals, VLDL removal is also impaired. The increase in LDL and/or VLDL remnant formation, regardless of prevailing plasma lipid levels or the severity of diabetes, provides a source of cholesterol which may account for the atherogeneity of this disorder.

The effects of C1-719 on plasma lipid and lipoprotein concentrations have been examined in four patients with endogenous hypertriglyceridaemia maintained on an isocaloric diet for a period of 6 months. During therapy (400 mg/day) the mean plasma triglyceride and cholesterol concentrations were reduced by 35% and 15% respectively, while the administration of 800 mg/day reduced these by 49% and 31%. This hypolipidaemic effect was due to a reduction in the circulating level of very low density lipoproteins (VLDL) without a change in their composition. Before treatment the plasma VLDL triglyceride turnover, and FFA flux, were higher than that of normal subjects maintained on a similar diet. The plasma VLDL B-apoprotein turnover was similarly higher than in the controls. Administration of C1-719 decreased the plasma VLDL triglyceride turnover, FFA flux and VLDL B-approtein turnover. The drug reduced the insulin response following a glucose load with some decrease in glucose levels. The results suggest that the increase in plasma triglyceride concentration in patients with endogenous hypertriglyceridaemia is due to increased production of plasma VLDL triglyceride and its apoptein associated with an enhanced supply of FFA for hepatic triglyceride synthesis. C1-719 exerts a hypolipidaemic effect through a reduction of VLDL production, consequent upon inhibition of lipolysis as well as decreased synthesis of the apoprotein carrier. These effects could in part be explained by an improvement in peripheral tissue responsiveness to insulin and decreased exposure of the liver to high levels of insulin. However, a direct effect of the drug on adipose tissue and liver metabolism has to be considered.

Turnover kinetics of triglycerides (TG) and apolipoprotein-B (apo-B) of plasma very low density lipoprotein (VLDL) and their relationship to plasma VLDL composition and VLDL apo-B conversion to low density lipoprotein (LDL) were determined in age and weight-matched groups of normolipemic (NL) healthy subjects, patients with familial combined hyperlipidemia (FCHL) and patients with familial hypertriglyceridemia (FHTG). In NL subjects, a significant correlation as observed between VLDL TG or VLDL apo-B turnover rate and its circulating mass, suggesting that the plasma level of VLDL was determined by the secretion rate of VLDL TG and apo-B. The positive significant correlation between VLDL TG and apo-B also suggests that the production of these moieties was integrated at the synthetic and/or secretory sites to maintain the ratio of TG to apo-B in plasma VLDL. In moderately obese NL subjects, proportionate increases in VLDL TG and apo-B turnover rates resulted in enhanced secretion of VLDL particles. Both groups with genetic hypertriglyceridemia had increased VLDL TG and VLDL apo-B turnover rates. This increase accounted for the increase in circulating VLDL TG and apo-B mass. In patients with FCHL, turnover rates of VLDL TG and apo-B were equally increased, hence, the ratios between major VLDL constituents were within normal limits. On the other hand, the increase in VLDL TG turnover in patients with FHTG was disproportionately greater than that of apo-B resulting in a higher ratio of TG to other VLDL components. In NL subjects, approximately 72% of VLDL apo-B released into plasma was converted to LDL. This conversion correlated positively with VLDL apo-B turnover rate and inversely with VLDL TG turnover rate. Formation of LDL from VLDL was significantly greater in the obese individuals. In FCHL, conversion of VLDL to LDL represented the major pathway for VLDL apo-B catabolism. The increased VLDL apo-B load was predominantly catabolized to LDL. The greater increase in VLDL TG turnover relative to apo-B in FHTG, on the other hand, resulted in a smaller fraction of VLDL apo-B recovered in LDL, most of the VLDL apo-B being removed via a pathway that did not involve this conversion. We conclude that the composition and metabolic fate of plasma VLDL may be greatly influenced by the secretion rates of VLDL TG and apo-B. If VLDL conversion to LDL and the subsequent catabolism of the latter provides a major route for delivery of cholesterol ester to peripheral tissues, then the increased LDL production in FCHL compared to FHTG may account for a higher cardiovascular risk.

As in women receiving oestrogens the administration of 17beta-oestradiol to ovariectomized female rats caused a rise in fasting plasma triglycerides and a fall in plasma glucose. Progesterone, on the other hand, had no significant effects. In the oestradiol treated rats, the portal vein basal insulin levels were slightly reduced. Oestradiol, however, had a marked suppressive effect on the alpha cells of the pancreas resulting in a greater reduction in basal glucagon and impaired glucagon response to alanine infusions. The relative insulin to glucagon (I/G) molar concentration ratio in portal vein blood was increased. Oestradiol also produced a dose dependent increase in the activity of the liver lipogenic enzymes, acetyl CoA carboxylase and fatty acid synthetase. On the other hand, the activity of the gluconeogenic rate limiting enzyme phosphoenol-pyruvate carboxykinase (PEPCK) was inhibited. The cross-over pattern of gluconeogenic intermediates confirmed inhibition of gluconeogenesis at this step, an effect which is similar to that induced by relative insulin 'excess'. Progesterone produced an increase in the portal vein insulin concentrations. Both the basal and the alanine-stimulated glucagon levels were also increased. The I/G molar ratio in portal vein blood of progesterone treated rats remained unaltered and the hepatic lipogenic and gluconeogenic enzyme activities were similar to control animals. These data suggest that insulin activity is increased relative to glucagon in the liver of oestradiol-treated rats due to the rise in portal vein I/G ratio. The changes in liver lipogenic and gluconeogenic enzymes and the alterations in fasting plasma triglycerides and glucose in response to oestrogens could be secondary to this effect.

Using I131 VLDL selectively labelled in the B-apoprotein and I125 LDL injected simultaneously into the patient we have derived some quantitative measures of VLDL and LDL metabolism in man. The effects of insulin resistance, associated with idiopathic hypertriglyceridaemia, adult onset diabetes and diabetic lipodystrophy on the metabolic behaviour of these molecules were also assessed. In the normal subjects 72-83% of the total daily plasma VLDL B-apoprotein flux was metabolised via a pathway which involved its ultimate conversion to plasma LDL, while 21-28% was degraded without such conversion. The amount of B-apoprotein metabolised by either of these routes was proportionate to the flux rate and the two pathways accounted for the total VLDL B-apoprotein removed from the plasma. In patients with idiopathic hypertriglyceridaemia and in the adult onset diabetics the total plasma VLDL B-apoprotein flux was higher than normal, indicating increased production of this apoprotein. On the other hand, the flux rate of plasma VLDL B-apoprotein in the patients with diabetic lipodystrophy was normal, suggesting that the increase in the circulating mass of these molecules was due to impaired clearance. In all the patients, however, the fractions of the total flux either converted to LDL or degraded were lower than normal, suggesting that insulin resistance limited the removal of this apoprotein by these pathways. The results also indicate that a fraction of the total VLDL removed from the plasma has been retained in an extravascular compartment, possibly representing VLDL molecules trapped in the vascular structures. In the control and the insulin resistant subjects the quantity of LDL apoprotein catabolised per day agreed closely with the amount derived from VLDL B-apoprotein conversion, suggesting that VLDL-B-apoprotein serves as the main source of LDL apoprotein. In patients with idiopathic hypertriglyceridaemia and in adult onset diabetics the absolute turnover rate of plasma LDL apoprotein was higher than normal, while in the lipodystrophic patients it was reduced. It is suggested that the increase in LDL turnover seen in the former groups could be an additive factor in the deposition of lipid rich material in arterial walls.

The role of the adrenal cortex in the pathogenesis of hypertriglyceridaemia associated with the intake of oral contraceptive agents containing oestrogen has been investigated in rats. Bilateral adrenalectomy reduced the activity of hepatic enzymes regulating lipogenesis (acetyl CoA carboxylase, fatty acid synthetase) and decreased plasma triglyceride concentrations. On the other hand, the administration of high dosage corticosterone induced the activity of hepatic enzymes with consequent elevation in serum triglyceride levels. In animals with intact adrenals the administration of oestradiol: (a) raised plasma triglyceride levels, (b) enhanced the activity of hepatic enzymes, and (c) increased the adrenal cortex:body weight ratio. The effects (a) and (b) were not observed when both adrenals were removed prior to oestrogen therapy. High dosage corticosterone replacement was found to be essential for the oestradiol to produce its effects on hepatic enzymes and plasma triglyceride levels. The results suggest a regulatory role for the adrenal cortex in the homeostasis of plasma triglyceride concentration and that the hypertriglyceridaemia induced by the oestrogen containing preparations might be secondary to alterations in adrenocortical function.

Studies were performed to evaluate the relative importance of enhanced adipose tissue lipolysis and increased insulin levels in modulating hepatic VLDL production in patients with endogenous hypertriglyceridaemia. Eight control subjects and nine patients with hypertriglyceridaemia were investigated. The latter group comprised four patients with idiopathic hypertriglyceridaemia, three maturity onset diabetics, and two siblings with diabetic lipodystrophy. Each individual's plasma VLDL was selectively labelled with I131 in the apoprotein moiety and then reinjected to assess the turnover of these molecules. This was correlated with the insulin response to an oral glucose load and with the plasma FFA flux measured by a continuous infusion of 14C palmitate. In the patients with idiopathic hypertriglyceridaemia and in the adult onset diabetics, plasma VLDL-appoprotein turnover was increased suggesting enhanced hepatic production of these molecules. Although the insulin levels in these patients were higher than normal, no significant correlation was demonstrable between the plasma insulin and the turnover of VLDL-B-apoprotein. Furthermore, in the two patients with lipo-dystrophy the turnover of plasma VLDL was within the normal range, whereas the plasma insulin responses were the highest among all the patients. These results suggest that hyperinsulinaemia alone is not sufficient to account for the increased VLDL production seen in some of our patients. The plasma FFA flux was raised in the patients with idiopathic hypertriglyceridaemia and in the maturity onset diabetics, and was within the normal range in the two patients with lipodystrophy. Indded, in all the subjects studied a significant correlation was observed between the turnover of plasma VLDL-B-apoprotein and the plasma FFA flux. The results thus indicate that the rate of FFA release to plasma constitutes the predominant factor in determining hepatic output of VLDL and that in the majority of patients with endogenous hypertriglyceridaemia the increased FFA flux resulting from insulin resistance in adipose tissue could effectively increase VLDL production. This process appears to be independent of the prevailing insulin levels, and could occur in the presence of insulin resistance in the liver. The latter, however, could be responsible for the impaired glucose tolerance observed in some patients.

Background: For decades, research efforts have tried to uncover the underlying genetic basis of human susceptibility to a variety of diseases. Linkage studies have resulted in highly replicated findings and helped identify quantitative trait loci (QTL) for many complex traits; however identification of specific alleles accounting for linkage remains elusive. The purpose of this study was to determine whether with a sufficient number of variants a linkage signal can be fully explained. Method: We used comprehensive fine-mapping using a dense set of single nucleotide polymorphisms (SNPs) across the entire quantitative trait locus (QTL) on human chromosome 7q36 linked to plasma triglyceride levels. Analyses included measured genotype and combined linkage association analyses. Results: Screening this linkage region, we found an over representation of nominally significant associations in five genes (MLL3, DPP6, PAXIP1, HTR5A, INSIG1). However, no single genetic variant was sufficient to account for the linkage. On the other hand, multiple variants capturing the variation in these five genes did account for the linkage at this locus. Permutation analyses suggested that this reduction in LOD score was unlikely to have occurred by chance (p = 0.008). Discussion: With recent findings, it has become clear that most complex traits are influenced by a large number of genetic variants each contributing only a small percentage to the overall phenotype. We found that with a sufficient number of variants, the linkage can be fully explained. The results from this analysis suggest that perhaps the failure to identify causal variants for linkage peaks may be due to multiple variants under the linkage peak with small individual effect, rather than a single variant of large effect. [ABSTRACT FROM AUTHOR]