Rol del enterocito en la dislipidemia de la diabetes mellitus tipo 2 / Role of the enterocyte in type 2 diabetes mellitus associated dyslipidemia

En la diabetes mellitus tipo 2 el aumento en la producción de quilomicrón en el estado post-prandial se asocia a mayor riesgo cardiovascular. La evidencia actual posiciona al enterocito como actor principal en la dislipemia de la diabetes mellitus tipo 2 debido a que aumenta la producción de apolipoproteína B-48 en respuesta a una elevación de ácidos grasos libres y glucosa. El metabolismo del quilomicrón se encuentra regulado por múltiples factores independientes además de la ingesta de grasa alimentaria. Entre estos factores se destacan las hormonas intestinales, como el péptido similar al glucagón tipo 1 que disminuye la producción de apolipoproteína B-48 y el péptido similar al glucagón tipo 2 que la aumenta. Por otro lado, la insulina inhibe de forma aguda la producción de quilomicrón en el sujeto sano mientras que en la diabetes mellitus tipo 2, este efecto está ausente. La comprensión de los factores reguladores emergentes de la secreción de quilomicrón permite vislumbrar nuevos mecanismos de control en su metabolismo y aportar estrategias terapéuticas focalizadas en la hiperlipidemia posprandial en la diabetes mellitus tipo 2 con la reducción del riesgo cardiovascular.

In type 2 diabetes mellitus there is an overproduction of chylomicron in the postprandial state that is associated with increased cardiovascular risk. Current evidence points out a leading role of enterocyte in dyslipidemia of type 2 diabetes mellitus, since it increases the production of apolipoprotein B-48 in response to a raise in plasma free fatty acids and glucose. The chylomicron metabolism is regulated by many factors apart from ingested fat, including hormonal and metabolic elements. More recently, studies about the role of gut hormones, have demonstrated that glucagon-like peptide-1 decreases the production of apolipoprotein B-48 and glucagon-like peptide-2 enhances it. Insulin acutely inhibits intestinal chylomicron production in healthy humans, whereas this acute inhibitory effect on apolipoprotein B-48 production is blunted in type 2 diabetes mellitus. Understanding these emerging regulators of intestinal chylomicron secretion may offer new mechanisms of control for its metabolism and provide novel therapeutic strategies focalized in type 2 diabetes mellitus postprandial hyperlipidemia with the reduction of cardiovascular disease risk.

Effect of Pitavastatin Treatment on ApoB-48 and Lp-PLA2 in Patients with Metabolic Syndrome: Substudy of PROspective Comparative Clinical Study Evaluating the Efficacy and Safety of PITavastatin in Patients with Metabolic Syndrome

BACKGROUND: Apolipoprotein (Apo) B-48 is an intestinally derived lipoprotein that is expected to be a marker for cardiovascular disease (CVD). Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a vascular-specific inflammatory marker and important risk predictor of CVD. The aim of this study was to explore the effect of pitavastatin treatment and life style modification (LSM) on ApoB-48 and Lp-PLA2 levels in metabolic syndrome (MS) patients at relatively low risk for CVD, as a sub-analysis of a previous multi-center prospective study. METHODS: We enrolled 75 patients with MS from the PROPIT study and randomized them into two treatment groups: 2 mg pitavastatin daily+intensive LSM or intensive LSM only. We measured the change of lipid profiles, ApoB-48 and Lp-PLA2 for 48 weeks. RESULTS: Total cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and ApoB-100/A1 ratio were significantly improved in the pitavastatin+LSM group compared to the LSM only group (P≤0.001). Pitavastatin+LSM did not change the level of ApoB-48 in subjects overall, but the level of ApoB-48 was significantly lower in the higher mean baseline value group of ApoB-48. The change in Lp-PLA2 was not significant after intervention in either group after treatment with pitavastatin for 1 year. CONCLUSION: Pitavastatin treatment and LSM significantly improved lipid profiles, ApoB-100/A1 ratio, and reduced ApoB-48 levels in the higher mean baseline value group of ApoB-48, but did not significantly alter the Lp-PLA2 levels.

Experimental study of Apobec-1 recombinant adenovirus in treatment of renal hyperlipemia / 安徽医科大学学报

Objective To explore the effect of the liver acquired expression of apolipoprotein B editing catalytic polypeptide-1 (Apobec-1) on hyperlipidemia of renal disease. Methods Thirty healthy ordinary level male New Zealand rabbits were randomly divided into three groups: sham operation group, nephropathy group, and Apobec-1 treatment group (Each group has 10 rabbits). Adapt feeding for one week, nephropathy group and Apobec-1 treat-ment group underwent left nephrectomy, and one week later, adriamycin (4 mg / kg) was used to construct the ne-phropathy model by ear vein injection. The eleventh week after operation, apobec-1 recombinant adenovirus (1 × 1013 Virus/ kg) was injected by ear vein in apobec-1 treatment group. The twelfth week after operation, all rabbits were sacrificed. Right kidney, liver, blood and 24h urine were left. In three groups, 24 hour urinary protein (24UPr), albumin (Alb), blood urea nitrogen (BUN), creatinine (Cr), blood lipid were detected. Renal pa-thology was observed by HE staining. Expressions of liver apobec-1, apolipoprotein B48(ApoB48)were observed by Western blot. Results ① Compared with the sham operation group, nephropathy group showed that 24UPr, BUN, Cr, total cholesterol (TC), total triglyceride (TG), very low density lipoprotein (VLDL-C), low density lipoprotein (LDL-C), apolipoprotein B100 (ApoB100) were increased(P < 0. 05), but Alb was decreased(P <0. 05). ② Compared with the nephropathy group, Apobec-1 treatment group showed that TC, TG, VLDL-C, LDL-C, ApoB100, ApoB48 were decreased(P < 0. 05). ③ Compared with the sham operation group, Apobec-1 treat-ment group showed that 24UPr, BUN, Cr were increased( P < 0. 05), but Alb, ApoB48 were decreased( P <0. 05). ④ Compared with the sham operation group and nephropathy group, Apobec-1 treatment group showed that the expression of Apobec-1 and ApoB48 were up-regulated (P < 0. 01). Conclusion When liver aquires expres-sion of Apobec-1 in hyperlipidemia of renal disease, it can reconstruct ApoB mRNA, increase the synthesis of ApoB48-lipoprotein, and play a certain lipid-lowering effect.

A new sight into mechanism of hypertriglyceridemia induced by hypothyroidism / 中华内分泌代谢杂志

Hypertriglyceridemia is one of the clinical manifestations of hypothyroidism.Besides regulating thyroid hormone axis,thyroid stimulating hormone (TSH) also has the effect on up-regulated expression of inflammatory cytokines.Synthesis of inflammatory factors can promote the expression of apolipoprotein B48 (ApoB48) in intestinal mucosal epithelial cells,suggesting that TSH may up-regulate the expression of ApoB48 by inducing inflammation; while theoratically,low-level of thyroid hormones can inhibit the synthesis of ApoB48.At the same time,since ApoB48 is the important cause of hypertriglyceridemia,there is a contradiction that it is difficult to explain the clinical phenomenon of hypertriglyceridemia induced by hypothyroidism.Therefore,hypothyroidism may affect the expression of ApoB48 by high level of TSH and low level of thyroid hormones,leading to hypertriglyceridemia.

Effect of Omega-3 Fatty Acids on Low Density Lipoprotein Subfraction, Adiponectin and Apolipoprotein B in Type 2 Diabetic Patients

BACKGROUND: Omega-3 fatty acids derived from fish oil have been reported to exert a beneficial effect on reducing cardiovascular disease. Reports about their mechanism have generated several interesting findings, including a change in small dense low density lipoprotein (sdLDL) cholesterol proportion, adiponectin, and apolipoprotein B (apoB), in addition to changes in the lipid profile. The principal objective of our study was to evaluate the effects of omega-3 fatty acids on plasma sdLDL, adiponectin, apoB100, and B48 in type 2 diabetic patients with hypertriglyceridemia. METHODS: We randomized 28 type 2 diabetic patients in a placebo-controlled, double-blind trial to receive either omega-3 fatty acids or placebo, both administered at a dose of 4 g daily for 12 weeks. LDL subfractions prior to and after treatment were separated via low-speed ultracentrifugation and analyzed via immunoelectrophoresis. Adiponectin, apoB100, and B48 levels were measured using an ELISA kit. RESULTS: sdLDL proportions were reduced in the omega-3 fatty acids group by 11% after 12 weeks of treatment (n = 17, P = 0.001), and were reduced by 4% in the control group (n = 11, P = 0.096). The patients receiving the omega-3 fatty acids evidenced a significant reduction in the levels of triglyceride (P = 0.001), apoB100, and B48 after 12 weeks (P = 0.038 and P = 0.009, respectively) relative to the baseline. Omega-3 fatty acids supplementation increased fasting blood glucose (P = 0.011), but the levels of HbA1c in each group did not change to a statistically significance degree. The adiponectin value was not reduced in the omega-3 fatty acids group (P = 0.133); by way of contrast, the placebo group evidenced a significant reduction in adiponectin value after 12 weeks (P = 0.002). CONCLUSION: Omega-3 fatty acid treatment proved effective in the reduction of atherogenic sdLDL and apoB in type 2 diabetic patients (Clinical trials reg. no. NCT 00758927, clinicaltrials.gov).