Treatment with mipomersen reduces levels of apoB-containing lipoproteins by increasing fractional removal of VLDL and LDL-apoB without reducing vldl-apob secretion

The current study assessed in vivo the effect of insulin on triglyceride-rich lipoprotein (TRL) production by rat liver. Hepatic triglyceride and apolipoprotein B (apoB) production were measured in anesthetized, fasted rats injected intravenously with Triton WR-1339 (400 mg/kg). After intravascular catabolism was blocked by detergent treatment, glucose (500 mg/kg) was injected to elicit insulin secretion, and serum triglyceride and apoB accumulation were monitored over the next 3 h. In glucose-injected rats, triglyceride secretion averaged 22.5 ± 2.1 μg · ml−1· min−1, which was significantly less by 30% than that observed in saline-injected rats, which averaged 32.1 ± 1.4 μg · ml−1· min−1. ApoB secretion was also significantly reduced by 66% in glucose-injected rats. ApoB immunoblotting indicated that both B100 and B48 production were significantly reduced after glucose injection. Results support the conclusion that insulin acts in vivo to suppress hepatic very low density lipoprotein (VLDL) triglyceride and apoB secretion and strengthen the concept of a regulatory role for insulin in VLDL metabolism postprandially.

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The Effect of a Six-Month Exercise Program on Very Low-Density Lipoprotein Apolipoprotein B Secretion in Type 2 Diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-031036 ◽

2004 ◽

Vol 89 (2) ◽

pp. 688-694 ◽

Cited By ~ 61

Author(s):

Saima Alam ◽

Michael Stolinski ◽

Claire Pentecost ◽

Massoud A. Boroujerdi ◽

Richard H. Jones ◽

...

Keyword(s):

Type 2 Diabetes ◽

Apolipoprotein B ◽

Low Density Lipoprotein ◽

Exercise Program ◽

Density Lipoprotein ◽

Secretion Rate ◽

Very Low Density Lipoprotein ◽

Supervised Exercise ◽

Apob Secretion

The dyslipidemia and insulin resistance of type 2 diabetes can be improved by aerobic exercise. The effect of 6 months supervised exercise on very low-density lipoprotein (VLDL) apolipoprotein B metabolism was investigated in patients with type 2 diabetes. Moderately obese patients (n = 18) were randomized into supervised (n = 9) and unsupervised (n = 9) exercise groups. All patients were given a training session and a personal exercise program and asked to exercise four times per week at 70% maximal oxygen uptake for 6 months. Patients in the supervised group had a weekly session with an exercise trainer. VLDL apolipoprotein (apo)B metabolism was measured with an infusion of 1-13C leucine before and after 6 months of the exercise program. Supervised exercise for 6 months resulted in a significant within-group decrease in percent hemoglobin A1c (P < 0.001), body fat (P < 0.004), nonesterified fatty acid (P < 0.04), and triglycerides (P < 0.05) and an increase in insulin sensitivity (P < 0.01). There was a decrease in VLDL apoB pool size (160.8 ± 42.6 to 84.9 ± 23.2 mg, P < 0.01) and VLDL apoB secretion rate (11.3 ± 2.6 to 5.5 ± 2.0 mg/kg·d, P < 0.05) with no change in fractional catabolic rate. In a between-group comparison, the decrease in VLDL apoB secretion rate in the supervised group did not achieve significance. This study demonstrates that in type 2 diabetes, a supervised exercise program reduces VLDL apoB pool size, which may be due to a decrease in VLDL apoB secretion rate.

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Abstract 573: Human Microrna-548p Decreases apoB Secretion and Lipid Synthesis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.573 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Liye Zhou ◽

Mahmood Hussain

Keyword(s):

Fatty Acid ◽

Untranslated Region ◽

Lipid Synthesis ◽

Hepatoma Cells ◽

Site Directed Mutagenesis ◽

Acid Oxidation ◽

Human Hepatoma ◽

Human Hepatoma Cells ◽

Apob Mrna ◽

Apob Secretion

Objective: MicroRNAs (miRs) play important regulatory roles in lipid and lipoprotein metabolism. ApoB, as the only essential scaffolding protein in the assembly of very low density lipoproteins, is a target to treat hyperlipidemia and atherosclerosis. We aimed to find out miRs that reduce apoB expression. Approach: Bioinformatics analyses predicted that hsa-miR-548p can interact with apoB mRNA.MiR-548p mimic and control were transfected in human and mouse hepatoma cell lines to test its role in regulating apoB secretion and mRNA expression levels. Site-directed mutagenesis was used to identify the interacting site of miR-548p in human apoB 3′-untranslated region. Fatty acid oxidation and lipid syntheses were examined in miR-548p overexpressing cells to investigate its function in lipid metabolism. Results: Experimentally, we observed that miR-548p significantly reduces apoB secretion from human hepatoma cells in time and dose dependent manner. Mechanistic studies showed that miR-548p interacts with the 3′-untranslated region of human apoB mRNA to enhance posttranscriptional degradation. Bioinformatics algorithms suggested two potential binding sites of miR-548p on human apoB mRNA. Site-directed mutagenesis studies revealed that miR-548p targets site II involving both seed and supplementary sequences. MiR-548p had no effect on fatty acid oxidation but significantly decreased lipid synthesis in human hepatoma cells by reducing the expression of HMGCR and ACSL4 enzymes involved in cholesterol and fatty acid synthesis. In summary, miR-548p reduces lipoprotein production and lipid synthesis by reducing expression of different genes in human hepatoma cells. Conclusion: These studies suggest that miR-548p could be useful in treating atherosclerosis, hyperlipidemia and hepatosteatosis.

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