Liraglutide Increases the Catabolism of Apolipoprotein B100–Containing Lipoproteins in Patients With Type 2 Diabetes and Reduces Proprotein Convertase Subtilisin/Kexin Type 9 Expression

Abstract

<a><b>OBJECTIVE:</b></a> Dyslipidemia observed in type 2 diabetes (T2DM) is atherogenic. Important features of diabetic dyslipidemia are increased levels of triglyceride-rich lipoproteins and small dense LDL particles which, all have apolipoprotein B100 (apoB100) as major apolipoprotein. This prompted us to study the effect of the GLP1 agonist, liraglutide, on the metabolism of apoB100 containing lipoproteins. <p><b>RESEARCH DESIGN AND METHODS</b>: We performed an <i>in vivo</i> kinetic study with stable isotopes (L-[1-<sup>13</sup>C] leucine) in 10 T2DM patients before and after 6-month treatment with liraglutide (1.2 mg/day). We also evaluated, in mice, the effect of liraglutide on the expression of genes involved in apoB100 containing lipoprotein clearance.</p> <p><b>RESULTS</b>: In T2DM patients, liraglutide treatment significantly reduced plasma apoB100 (0.93±0.13 vs. 1.09±0.11 g/L, p=0.011) and fasting triglycerides (1.76±0.37 vs. 2.48±0.69 mmol/L, p=0.005). The kinetic study showed a significant increase in indirect catabolism of VLDL<sub>1</sub>-apoB100 (4.11±1.91 vs. 2.96±1.61 day<sup>-1</sup>,p=0.005), VLDL<sub>2</sub>-apoB100 (5.17±2.53 vs. 2.84±1.65 day<sup>-1</sup>,p=0.008), IDL-apoB100 (5.27±2.77 vs. 3.74±1.85 day<sup>-1</sup>,p=0.017) and in catabolism of LDL-apoB100 (0.72±0.22 vs. 0.56±0.22 day<sup>-1</sup>,p=0.005). In mice, liraglutide increased lipoprotein lipase (LPL) gene expression and reduced Proprotein convertase subtilisin/kexin type 9 (PCSK9), Retinol Binding Protein 4 (RBP4) and Tumor Necrosis Factor alpha (TNF alpha) gene expression in adipose tissue, and decreased PCSK9 mRNA and increased LDL-receptor protein expression, in liver. In vitro, liraglutide directly reduced the expression of PCSK9 in the liver.</p> <p><b>CONCLUSIONS</b>: Treatment with liraglutide induces a significant acceleration of the catabolism of triglyceride-rich lipoproteins (VLDL<sub>1</sub>, VLDL<sub>2</sub>, IDL) and LDL. Liraglutide modifies the expression of genes involved in apoB100 containing lipoprotein catabolism. These positive effects on lipoprotein metabolism may reduce cardiovascular risk in T2DM.</p>

Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease

“…Interestingly, combined with the results of other studies that have linked variation at LPL as being associated with lower lipid levels and risk of CAD, our analysis suggests that targeting the LPL pathway may prevent NAFLD as well as other diseases such as hyperlipidemia and CAD without increasing the risk of other human diseases. Drugs targeting the LPL pathway under investigation for NAFLD include the angiopoietin-like protein-3 (ANGPTL3) inhibitors, 35 glucagon-like peptide-1 (GLP-1) receptor agonists, 36 and dual glucose-dependent insulinotropic peptide (GIP)/GLP-1 receptor agonists. 37 Drugs targeting obesity such as semaglutide were also recently associated with NASH resolution without worsening in liver fibrosis.…”

Cardiorenal mechanisms of action of glucagon-like-peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors

“…Separate studies with liraglutide administration for 6 months to 10 people with T2D (baseline HbA1c 9.6%, mean body mass index [BMI] 36.6 kg/m 2 ) revealed increased rates of catabolism of low-density lipoprotein (LDL)-and very-low-density lipoprotein (VLDL)-associated ApoB100 and decreased circulating levels of PCSK9, in people with 4 kg of weight loss and a reduction in mean HbA1c to 7.1%. 69 Consistent with these findings, tracer kinetic studies in 8 men with obesity and T2D revealed that treatment with once-daily lixisenatide for 4 weeks had a minimal impact on chylomicron production, yet increased the clearance of triglyceride-rich chylomicrons. 74 The relative contributions of distinct cell types linking GLP-1R signaling to the control of lipoprotein secretion or catabolism have not been conclusively identified, as the GLP-1R is not detected within enterocytes, hepatocytes, or renal epithelium.…”

“…68 Preclinical studies in high-fat diet-fed and ob/ ob mice demonstrated that 10 days of liraglutide administration reduced hepatic Pcsk9 and induced Ldlr/LDLR expression. 69 Acute intraduodenal administration of exenatide suppressed the appearance and production rate of triglyceride-rich lipoprotein apolipoprotein B-48 in humans, consistent with a role for GLP-1R signaling to control enterocyte lipoprotein secretion. 70 The suppression of postprandial triglycerides is independent of gastric emptying or insulin secretion in mice and humans, remains intact in people with or without T2D or obesity, and is not diminished with sustained GLP-1R agonism.…”

“…71,72 The underlying mechanisms reflect the reduction in chylomicron secretion; however, enhanced clearance of ApoB48 lipoproteins has also been demonstrated. 68,69,70,73 Attenuation of postprandial ApoB48 production was observed in people with T2D treated with liraglutide 1.2 mg daily for 6 months, in association with increased fractional clearance of ApoB48 assessed through kinetic studies using stable isotopic enrichment. 73 Notably, liraglutide also reduced HbA1c and body weight, confounding mechanistic interpretation of the data.…”

Association of serum apolipoprotein B with retinal neurovascular structural alterations in patients with type 2 diabetes: an optical coherence tomography angiography study

“…Multiple studies in several countries have confirmed that dyslipidemia is an important risk factor for diabetic retinopathy [5], and serum low-density lipoprotein cholesterol (LDL-C) levels are associated with an increased risk for progression to advanced retinopathy [6] and retinal neurovascular impairment in diabetic patients [7]. ApoB is the principal lipoprotein component of LDL-C [8], and abnormal metabolism of apoB is regarded as an important feature of diabetic dyslipidemia [9]. Recently, the total concentration of circulating apoB particles was recommended as a new indicator to assess the risk of atherosclerotic cardiovascular disease [10], which is the most serious diabetic complication.…”