# Protective Effect of Carvedilol Against Oxidative Stress Induced by Palmitic Acid in Primary Rat Hepatocytes

## TL;DR

Carvedilol protects liver cells from damage caused by palmitic acid by reducing oxidative stress, but it does not affect lipid buildup or endoplasmic reticulum stress.

## Contribution

This is the first study showing carvedilol protects hepatocytes from palmitate-induced cell death via reducing oxidative stress.

## Key findings

- Carvedilol reduced palmitic acid-induced cell death to control levels.
- Carvedilol increased expression of mitochondrial antioxidant enzymes Sod2 and Cat.
- Carvedilol did not affect endoplasmic reticulum stress or lipid accumulation.

## Abstract

Hepatocyte lipotoxicity (HL) is an important factor in the pathogenesis of Metabolic Dysfunction‐Associated Steatotic Liver Disease (MASLD). It is defined as the detrimental effects of exposure to (excessive) amounts of toxic lipid species, leading to increased mitochondrial β‐oxidation, oxidative stress (OxS), and organellar dysfunction. Carvedilol (CV) is a β‐adrenergic blocker with antioxidant properties. To elucidate whether CV protects hepatocytes against lipotoxicity induced by palmitic acid (PA) by reducing OxS and endoplasmic reticulum (ER) stress. Primary rat hepatocytes (rHep) were used. Lipotoxicity was induced by PA (1 mmol/L). Cell damage was evaluated by Sytox Green staining. Mitochondrial generation of reactive oxygen species (mROS) was assessed by MitoSox. mRNA and protein expression were measured by qPCR and Western blot, respectively. Lipid accumulation was measured by Oil Red O staining and triglyceride (TG) content. PA induced cell death in > 80% of cells and increased mROS generation. PA increased mRNA expression of ER stress markers CHOP and sXBP1 and slightly increased lipid accumulation. Expression of the β‐oxidation‐related gene Cpt1a was increased. CV (10 µmol/L) significantly reduced PA‐induced cell death to control levels (< 8% of total cells), and mROS generation and expression of the mitochondrial antioxidant enzymes Sod2 and Cat were increased by 40% by CV in the presence of PA. CV did not change the expression of ER stress markers. CV, added before PA, protects rHep against PA‐induced cytotoxicity by reducing OxS and increasing the expression of antioxidant enzymes without any additional protective effect on ER stress or lipid accumulation.

This is the first study demonstrating that CV protects against palmitate‐induced cell death in hepatocytes via scavenging reactive oxygen species without modulating lipid accumulation or reducing endoplasmic reticulum stress.