Platelets accelerate endoplasmic reticulum stress and promote hepatic steatosis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, characterized by endoplasmic reticulum (ER) stress, which impairs hepatic lipoprotein metabolism. Blood platelets can modulate cellular responses to ER stress and accumulate in the liver during MASLD, contributing to disease development through interaction with liver-resident (immune) cells. Given the role of platelets in modulating hepatic ER stress in vitro, this study aims to investigate their effects on hepatic ER stress and steatosis.

C57BL/6 mice (n = 6-12) were depleted for platelets and injected with tunicamycin (1 μg/g) to induce ER stress-induced hepatic steatosis. Hepatic platelet infiltration and activation was investigated by flow cytometry, ELISA, and electron microscopy. Livers were analyzed for ER stress markers by quantitative PCR, Western blotting, proteomics, and flow cytometry. Thereafter, platelet-hepatocyte co-cultures (n=4) and in vivo blocking of GPIbα (n = 5-10) were used for further mechanistic investigations.

Our study demonstrates that hepatic ER stress leads to 1.8-fold accumulation (p = 0.007) of platelets. Depletion of platelets decreased ER stress-induced liver steatosis by 35% (p <0.0001). Mechanistically, we found that platelet depletion ameliorated the initial ER stress response and increased the influx of neutrophils into the liver. Inhibiting the platelet-specific receptor glycoprotein 1bα (GPIbα) partly mimicked the effects of platelet depletion, leading to impaired hepatic platelet recruitment and reduced triglyceride accumulation.

This study reveals a new role of platelets in hepatic ER stress and the concomitant effect on hepatic steatosis.

This paper shows that blood platelets are capable of regulating specific metabolic functions in liver cells (so-called ER stress) and thereby contribute to the development of hepatic steatosis.