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The ferroptosis mediator ACSL4 fails to prevent disease progression in mouse models of MASLD
Carolin Angendohr1, Christiane Koppe1, Diran Herebian2
1Department of Gastroenterology, Hepatology and Infectious Diseases, Faculty of Medicine & Düsseldorf University Hospital, Heinrich-Heine-University, Düsseldorf, Germany.
Background:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an increasingly prevalent condition and a major risk factor for chronic liver damage, potentially leading to steatohepatitis and HCC. It is already known that patients with MASLD show increased systemic and hepatic iron concentrations as well as perturbed lipid metabolism, suggesting the involvement of ferroptosis in the development and progression of MASLD. Consequently, inhibition of ferroptosis represents a potential therapeutic option for patients with MASLD.
Methods:
We investigated whether liver parenchymal cell-specific deletion (LPC-KO) of the pro-ferroptotic gene acyl-CoA synthetase long-chain family member 4 (ACSL4LPC-KO) reduces MASLD onset and progression in mice. ACSL4LPC-KO and wild-type littermates were fed a choline-deficient high-fat diet (CD-HFD) or a Western diet for 20 weeks (CD-HFD and Western diet) or 40 weeks (CD-HFD only) to monitor MASLD progression and metabolic syndrome development.
Results:
In contrast to the recently published studies by Duan et al, our results show no significant differences between ACSL4LPC-KO and wild-type mice with regard to the development of MASLD or the progression of metabolic syndrome. Furthermore, no differences were observed in metabolic parameters (ie, weight gain, glucose tolerance test, hepatic steatosis) or MASLD-associated inflammatory response.
Conclusions:
Our analyses, therefore, suggest that loss of ACSL4 has no effect on the progression of MASLD induced by CD-HFD or the Western diet. The discrepancy between our and previously published results could be due to differences in the diets or the influence of a distinct microbiome, so the results obtained with hepatocyte-specific ACSL4LPC-KO should be taken with caution.
Insights
Investigating the role of ACSL4 in metabolic dysfunction-associated steatotic liver disease (MASLD), this study found no significant impact of its liver-specific deletion on MASLD progression or metabolic syndrome development in mice. These findings suggest ACSL4 inhibition may not be a viable therapeutic strategy for MASLD.
Area of Science:
- Hepatology
- Metabolic Diseases
- Cellular Biology
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing health concern linked to chronic liver damage, steatohepatitis, and hepatocellular carcinoma (HCC).
- MASLD is associated with increased iron and altered lipid metabolism, implicating ferroptosis in its pathogenesis.
- Targeting ferroptosis is a potential therapeutic avenue for MASLD.
Purpose of the Study:
- To determine if deleting the pro-ferroptotic gene acyl-CoA synthetase long-chain family member 4 (ACSL4) in liver parenchymal cells (LPC-KO) affects MASLD onset and progression.
- To evaluate the impact of ACSL4 deficiency on metabolic syndrome development in a mouse model of MASLD.
Main Methods:
- Mice with liver parenchymal cell-specific deletion of ACSL4 (ACSL4LPC-KO) and wild-type littermates were fed a choline-deficient high-fat diet (CD-HFD) or a Western diet.
- MASLD progression and metabolic syndrome development were monitored over 20 or 40 weeks.
Main Results:
- No significant differences were observed between ACSL4LPC-KO and wild-type mice in MASLD development or metabolic syndrome progression.
- Key metabolic parameters, including weight gain, glucose tolerance, and hepatic steatosis, showed no significant variations.
- MASLD-associated inflammatory responses did not differ between the experimental groups.
Conclusions:
- Loss of ACSL4 in hepatocytes does not appear to influence the progression of MASLD induced by CD-HFD or Western diets.
- Discrepancies with previous studies may stem from variations in diet composition or microbiome influence.
- Results from hepatocyte-specific ACSL4 deletion should be interpreted with caution due to potential confounding factors.
