The Metabolism of Low Density Lipoprotein in Endogenous Hypertriglyceridaemia

The metabolism of low density lipoprotein (LDL) was studied in eighteen hypertriglyceridaemic patients by injecting autologous radioiodinated LDL. Over 95 % of the label was bound to the protein moiety of LDL and therefore the metabolic data reflect the fate and distribution of LDL apoprotein (apo B). The hypertriglyceridaemic subjects included ten with Type V, five with Type IV, two with Type III and one with Type lib hyperlipoproteinaemia. For comparison identical studies were carried out in seven normal subjects and five patients with heterozygous familial hyperbetalipoproteinaemia (Type Ila). The groups differed considerably in mean LDL-cholesterol concentration. The patients with Type V lipoprotein pattern had significantly lower LDL-cholesterol concentration (mean 0.754 g/1) than the normal group (mean 1.237 g/1). Raised LDL-cholesterol levels were observed in all patients with heterozygous familial hyperbetalipoproteinaemia. The synthetic rate of LDL-apoprotein was found to be similar in all three groups (hypertriglyceridaemic, normal and hypercholesterolaemic). The highest synthetic rate was observed in the patient with Type lib pattern. However, the fractional catabolic rate (FCR) of LDL-apoprotein differed significantly. The highest mean FCR was found in the Type V group (0.65 ± 0.17 day^-1) compared with 0.41 ± 0.09 day^-1 in the normal group and 0.185 + 0.05 day^-1 in the Type Ila group. A strong inverse correlation was found between FCR and LDL apoprotein concentration in the whole series (r = - 0.90, p < 0.001) as well as within the Type V group (r = - 0.87, p < 0.01). These data indicate that the low plasma levels of LDL frequently observed in patients with very high plasma triglyceride levels are due to a high removal rate of LDL in these patients rather than to abnormal LDL synthesis.     

Determinants of fasting plasma triglyceride levels: metabolism of hepatic and intestinal lipoproteins

The contribution of the kinetics of exogeneous and endogenous lipoproteins in determining the level of triglyceride in fasting plasma was assessed in a group of 19 normolipidaemic and hypertriglyceridaemic subjects. From data derived during a 9-h infusion of [15N]-glycine, we have assessed very low density lipoprotein apolipoprotein B production, and from data analysed by kinetic modelling obtained following ingestion of retinol and triolein, we have assessed chylomicron and chylomicron remnant clearance in a group of 19 normolipidaemic and hypertriglyceridaemic subjects. A strong positive correlation was observed between the fasting plasma triglyceride level and the reciprocal of the apolipoprotein B fractional synthetic rate (r = 0.83, P less than 0.01). A positive correlation was also found with the rate of clearance of chylomicron remnants (Sf 20-400; r = 0.87, P less than 0.01) and of chylomicrons (Sf greater than 400; r = 0.69, P less than 0.01). No correlation was found between the fasting plasma triglyceride level and either of the plasma post-heparin lipolytic activities. Multivariate analysis revealed that 95% of the variance in triglyceride levels could be explained by the apolipoprotein B fractional synthetic rate and the chylomicron remnant clearance rate. The strong correlation between chylomicron remnant clearance, a measure of exogenous lipid metabolism, and fasting (hence, endogenous) plasma triglyceride levels suggests that remnants of chylomicrons and very low density lipoproteins share some common components of the removal process.     

瘦素与充血性心力衰竭

瘦素是与肥胖密切相关的内分泌激素 ,但目前对瘦素的研究已超越肥胖的范畴 ;许多研究表明 ,瘦素与心血管疾病关系密切 ,而且可能参与了充血性心力衰竭分解代谢等病理生理过程。     

SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis

Despite their common ability to activate intracellular signaling through CD80/CD86 molecules, cytotoxic T lymphocyte antigen 4 (CTLA-4)-Ig and CD28-Ig bias the downstream response in opposite directions, the latter promoting immunity, and CTLA-4-Ig tolerance, in dendritic cells (DCs) with opposite but flexible programs of antigen presentation. Nevertheless, in the absence of suppressor of cytokine signaling 3 (SOCS3), CD28-Ig—and the associated, dominant IL-6 response—become immunosuppressive and mimic the effect of CTLA-4-Ig, including a high functional expression of the tolerogenic enzyme indoleamine 2,3-dioxygenase (IDO). Here we show that forced SOCS3 expression antagonized CTLA-4-Ig activity in a proteasome-dependent fashion. Unrecognized by previous studies, IDO appeared to possess two tyrosine residues within two distinct putative immunoreceptor tyrosine-based inhibitory motifs, VPY₁₁₅CEL and LLY₂₅₃EGV. We found that SOCS3—known to interact with phosphotyrosine-containing peptides and be selectively induced by CD28-Ig/IL-6—would bind IDO and target the IDO/SOCS3 complex for ubiquitination and subsequent proteasomal degradation. This event accounted for the ability of CD28-Ig and IL-6 to convert otherwise tolerogenic, IDO-competent DCs into immunogenic cells. Thus onset of immunity in response to antigen within an early inflammatory context requires that IDO be degraded in tolerogenic DCs. In addition to identifying SOCS3 as a candidate signature for mouse DC subsets programmed to direct immunity, this study demonstrates that IDO undergoes regulatory proteolysis in response to immunogenic stimuli.