AMPK‐SIRT1‐independent inhibition of ANGPTL3 gene expression is a potential lipid‐lowering mechanism of metformin.

AMPK‐SIRT1‐independent inhibition of ANGPTL3 gene expression is a potential lipid‐lowering mechanism of metformin.

Lin Li; Burke Jamie; Venkatesh Sahana; Sadana Prabodh

Journal of Pharmacy & Pharmacology

2019

2019-09

Objectives: Hypertriglyceridaemia enhances cardiovascular disease risk in patients with diabetes. Lipoprotein lipase (LPL) regulates plasma triglyceride levels by hydrolysing chylomicrons and very‐low‐density lipoprotein (VLDL). Metformin, an antidiabetic drug, improves plasma lipids including triglycerides. We examined metformin's regulation of angiopoietin‐like 3 (ANGPTL3), a liver‐derived secretory protein with LPL inhibitory property. Methods: Using HepG2 cells, a human hepatocyte cell line, the effects of metformin on ANGPTL3 gene and protein expression were determined. The role of AMPK‐SIRT1 pathway in metformin regulation of ANGPTL3 was determined using pharmacological, RNAi and reporter assays. Metformin regulation of ANGPTL3 expression was also examined in sodium palmitate‐induced insulin resistance. Key findings: Metformin and pharmacological activators of AMPK and SIRT1 inhibited the expression of ANGPTL3 in HepG2 cells. Pharmacological or RNAi‐based antagonism of AMPK or SIRT1 failed to affect metformin inhibition of ANGPTL3. AMPK‐SIRT1 activators and metformin exhibited distinct effects on the expression of ANGPTL3 gene luciferase reporter. Sodium palmitate‐induced insulin resistance in cells resulted in increased ANGPTL3 gene expression which was suppressed by pretreatment with metformin. Conclusions: Metformin inhibits ANGPTL3 expression in the liver in an AMPK‐SIRT1‐independent manner as a potential mechanism to regulate LPL and lower plasma lipids. [ABSTRACT FROM AUTHOR]

angiopoietin‐like 3; diabetes; dyslipidaemia; lipoprotein lipase; metformin

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

1421-1428

9

71