# Hepatic–vascular crosstalk via GRK2: fenofibrate improves endothelial function by restoring lipid metabolism and NO signaling in obese mice

## TL;DR

Fenofibrate improves blood vessel function in obese mice by boosting nitric oxide and fixing fat metabolism through liver and vascular signaling.

## Contribution

This study reveals fenofibrate's novel role in restoring endothelial function via LKB1/AMPK/Akt activation and reduced hepatic GRK2 activity in obesity.

## Key findings

- Fenofibrate restored endothelial-dependent relaxation and increased nitric oxide production in obese mice.
- Fenofibrate reduced hepatic and plasma triglycerides, improving lipid metabolism in obese mice.
- Fenofibrate suppressed hepatic GRK2 activity, which may contribute to improved vascular function.

## Abstract

Obesity is often linked to endothelial dysfunction, a key factor in the development of cardiovascular and metabolic diseases. Reduced nitric oxide (NO) bioavailability is a defining feature of this condition, yet its underlying mechanisms and possible therapeutic targets remain unclear. Fenofibrate, a peroxisome proliferator-activated receptor-α (PPARα) agonist, is widely used to regulate lipid metabolism; however, its influence on vascular function and associated molecular pathways is not fully established. This study examined the effects of fenofibrate on vascular reactivity in high-fat diet (HFD)-induced obese mice, focusing on endothelial NO production and its upstream regulators.

Male Institute of Cancer Research mice were fed either a standard diet (SD) or an HFD for 12 weeks. Two weeks before the end of the feeding period, mice were treated with fenofibrate (25 mg/kg/day) or vehicle, forming four groups: SD, SD with fenofibrate (SD-FF), HFD, and HFD with fenofibrate (HFD-FF). Lipid profiles, aortic vascular function, and NO production were evaluated. Phosphorylation levels of liver kinase B1 (LKB1), AMP-activated protein kinase (AMPK), and Akt were analyzed, along with G protein-coupled receptor kinase 2 (GRK2) expression and activity in the aorta and liver.

HFD-FF mice showed markedly lower hepatic and plasma triglyceride levels than HFD mice, indicating improved lipid metabolism. Endothelial-dependent relaxation, which was impaired in HFD mice, was markedly restored in HFD-FF mice, accompanied by increased basal NO production. Aortic phosphorylation of LKB1, AMPK, and Akt was enhanced in HFD-FF mice relative to HFD mice, whereas aortic GRK2 activity remained unchanged. In the liver, GRK2 expression was elevated in HFD and HFD-FF groups compared with SD mice, but GRK2 activity was markedly increased in HFD mice and notably reduced in HFD-FF mice.

Fenofibrate improves endothelial-dependent relaxation and NO production in HFD-induced obese mice, likely through activation of the LKB1/AMPK/Akt pathway. The suppression of hepatic GRK2 activity by fenofibrate may contribute to better lipid metabolism, thereby promoting the recovery of vascular function.