# Endoplasmic reticulum stress enhances unsaturated fatty acid-induced hepatocyte injury in human pluripotent stem cell-derived hepatic culture

## TL;DR

This study shows that combining unsaturated fatty acids with endoplasmic reticulum stress causes liver cell death, highlighting a new mechanism in fatty acid-induced liver damage.

## Contribution

The study reveals that unsaturated fatty acids alone do not cause liver cell death but become toxic when combined with ER stress.

## Key findings

- Unsaturated fatty acids alone do not induce cell death or ER stress in hepatocytes.
- Combining unsaturated fatty acids with ER stress inducers leads to significant hepatocyte death.
- ER stress and unsaturated fatty acids together suppress fatty acid synthesis enzymes.

## Abstract

The liver is a central organ involved in lipid metabolism. Hepatocytes synthesize fatty acids and triglycerides under conditions of excess energy while decomposing fats by β-oxidation under conditions of energy deficiency. When fatty acid metabolism is impaired due to metabolic syndrome, excessive lipid accumulation in the liver increases the risk of fatty liver disease, chronic hepatitis, and liver cancer. Excessive fat accumulation causes various types of cell damage, such as oxidative stress, which causes lipotoxicity. There is a difference in lipotoxicity between saturated and unsaturated fatty acids among various fatty acids, and saturated fatty acids are more toxic. However, there are still many unknowns about the role of unsaturated fatty acids in steatohepatitis remains unclear.

In the present study, we evaluated the lipotoxicity of saturated and unsaturated fatty acids in a human induced pluripotent stem (iPS) cell-derived hepatocyte culture system. After inducing the differentiation of hepatic progenitor cells and hepatocytes from human iPS cells, palmitic and oleic acids were added. Tunicamycin and thapsigargin were added to induce endoplasmic reticulum (ER) stress. Cell viability and gene expression were analyzed.

When a saturated fatty acid (palmitic acid) was added to human iPS cell-derived hepatocytes, fatty acids alone induced cell death and expression of ER stress-related factors. However, unsaturated fatty acids (such as oleic acid) alone do not exhibit such activity. When oleic acid and ER stress inducers (tunicamycin and thapsigargin) were added simultaneously, strong induction of cell death was observed. Furthermore, the addition of unsaturated fatty acids and the induction of ER stress strongly suppressed the expression of enzymes in the fatty acid synthesis system. These results indicated that saturated fatty acid accumulation induced ER stress, whereas unsaturated fatty acid accumulation alone did not induce ER stress.

The combination of unsaturated fatty acid accumulation and ER stress induces hepatocyte death, thus indicating the importance of endoplasmic reticulum stress in the process of fatty acid-induced cell death.

The online version contains supplementary material available at 10.1186/s12876-026-04616-9.