FGF1 ameliorates hepatic steatosis through acute activation of the unfolded protein response and VLDL production

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious chronic liver disease with limited therapeutic options. Fibroblast growth factor (FGF) analogs show promising therapeutic benefits for MASLD, yet the underlying mechanisms remain incompletely understood. Here, we studied the mechanism underlying the anti-steatotic properties of FGF1, the prototype member of the FGF family.

The effect of FGF1 was studied in human and rodent hepatocytes and in obese mouse models exhibiting acute or chronic endoplasmic reticulum (ER) stress characteristic of MASLD. Metabolic analysis and proteomics were applied to evaluate liver physiology, ER stress and signaling.

We show that FGF1 reduces hepatic triglyceride (TG) levels in obese mice (51%, p <0.01, n = 8) via acute stimulation of very-low-density lipoprotein (VLDL, 3.9-fold, p <0.01, n = 8) secretion in an ER stress-dependent manner. This anti-steatotic effect was independent of adipose FGF receptor 1, which is required for the glucose-lowering effect of FGF1. Mechanistically, activation of the unfolded protein response (UPR), resulting in stabilization of apolipoprotein B (ApoB, 1.8-fold, p <0.01, n = 8), the main structural protein component of atherogenic lipoprotein particles, was identified as the key mechanism by which FGF1 drives VLDL secretion. Post-translational control of ApoB by FGF1 was potentiated by pre-existing ER stress. FGF1 stimulated major regulators of protein synthesis, and during ER stress, all three branches of the UPR were activated. In ER stress-primed lean mice, FGF1 adopted novel TG secretion activity (2.2-fold, p <0.05, n = 6). Conversely, alleviation of ER stress in obese mice suppressed FGF1-stimulated VLDL-TG production (49%, n = 11, p <0.05).

These results define ER stress-dependent modulation of VLDL secretion as a mechanism underlying the anti-steatotic activity of FGF1. Targeting the FGF-UPR pathway may thus have therapeutic potential for treating MASLD.

Fibroblast growth factors show therapeutic potential in both preclinical models and clinical trials for treating metabolic dysfunction-associated steatotic liver disease, a highly prevalent condition with limited treatment options. Identifying the mechanisms underlying their anti-steatotic effects may accelerate clinical development. Our finding that triglyceride secretion is the major driver of the anti-steatotic action of FGF1, together with the involvement of an adaptive unfolded protein response, provides deeper insight into the therapeutic potential of this pathway. These results also highlight possible implications for liver physiology and for the circulating lipoprotein profile, with relevance for both efficacy and safety considerations.