GLP-1 Drug Exenatide Combined with Glucagon Reduces Oxidative Stress in Fatty Liver Cells | Research

The takeaway

Exenatide alone reduced fat accumulation by 25% in liver cells, while combining it with glucagon cut oxidative stress markers by up to 24% through boosting antioxidant enzymes.

24% ROS reduction
Combined GLP-1 and glucagon receptor activation cut harmful reactive oxygen species by nearly a quarter in fat-laden liver cells

What the researchers found

Exenatide monotherapy reduced lipid accumulation in steatotic HepG2 cells by 25%. Combined glucagon and exenatide treatment significantly reduced markers of oxidative stress: reactive oxygen species (ROS) decreased by 24% and malondialdehyde (MDA, a lipid peroxidation marker) by 21%.

The oxidative stress reduction was associated with increased expression of two antioxidant enzymes — superoxide dismutase (SOD) and glutathione peroxidase (GPx) — but not catalase (Cat). This suggests dual GLP-1 and glucagon receptor activation enhances the cell's antioxidant defense capacity.

Why it matters

Fatty liver disease affects roughly 25% of the global population and can progress to liver inflammation, scarring, and even liver failure. Current treatment options are limited. The finding that combined GLP-1 and glucagon receptor activation reduces oxidative stress — a key driver of disease progression — provides mechanistic support for dual-agonist peptide drugs (like survodutide and other GLP-1/glucagon co-agonists) that are currently in clinical trials for MASLD.

How the study worked

Steatosis (fat accumulation) was induced in HepG2 hepatoma cells in vitro. Cells were then treated with exenatide (GLP-1 RA), glucagon, or the combination. Oxidative stress was assessed by measuring reactive oxygen species and malondialdehyde levels. Expression of three antioxidant enzymes (SOD, GPx, Cat) was quantified. Lipid accumulation was measured to assess the fat-reducing effect of treatment.

What this study cannot tell us

This is an in vitro study using a hepatoma cell line (HepG2), which may not fully represent normal liver cell behavior. The fat overload model is simplified compared to the complex metabolic environment of MASLD in living organisms. Specific doses of exenatide and glucagon used are not detailed in the abstract. No animal or human data are provided. The catalase non-response remains unexplained.

How to read the evidence

This is an in vitro cell culture study providing mechanistic insights. While the data clearly demonstrate the antioxidant effect of dual receptor activation, the findings have not been validated in animal models or humans.

When this study was published

Published in 2024, this study is recent and aligns with the current wave of clinical development of GLP-1/glucagon dual-agonist peptides for metabolic liver disease.

The bigger picture

The pharmaceutical industry is racing to develop GLP-1/glucagon dual-agonist peptides for obesity and fatty liver disease. Drugs like survodutide and other dual agonists aim to combine the appetite-suppressing effects of GLP-1 with glucagon's fat-burning and energy-expenditure effects. This study provides a cellular mechanism for why dual activation might be particularly beneficial for the liver — not just reducing fat, but actively protecting against the oxidative damage that drives MASLD progression.

Questions still open

Do GLP-1/glucagon dual agonists currently in clinical trials show similar antioxidant benefits in human liver tissue?
Why did the combination treatment increase SOD and GPx but not catalase expression?
Would the antioxidant benefits translate to slowing or preventing progression from fatty liver to steatohepatitis in vivo?

Common questions

What is exenatide and how is it related to GLP-1?

Exenatide is a synthetic version of a peptide originally found in Gila monster venom that mimics the hormone GLP-1. It activates GLP-1 receptors, helping regulate blood sugar, reduce appetite, and — as this study suggests — protect liver cells from fat-related damage. It was one of the first GLP-1 receptor agonists approved for type 2 diabetes.

Why combine a GLP-1 drug with glucagon for fatty liver disease?

GLP-1 reduces appetite and fat accumulation, while glucagon stimulates the liver to burn fat for energy. Together, they attack fatty liver from both directions — reducing new fat storage and increasing fat breakdown. This study adds a third benefit: the combination also reduces oxidative stress, which is what drives fatty liver to progress into more dangerous liver inflammation.

Read the original research

The impact of glucagon and exenatide on oxidative stress levels and antioxidative enzyme expression in in vitro induced steatosis in HepG2 cell culture.

Endokrynologia Polska, 75(4), 419-427

View on PubMed ↗Publisher’s paper ↗

Citation

Bołdys, Aleksandra; Bułdak, Łukasz; Skudrzyk, Estera; Machnik, Grzegorz; Okopień, Bogusław. (2024). The impact of glucagon and exenatide on oxidative stress levels and antioxidative enzyme expression in in vitro induced steatosis in HepG2 cell culture.. Endokrynologia Polska, 75(4), 419-427. https://doi.org/10.5603/ep.99891