MLKLK219R Mutation Protects Against Diet-Induced MASLD but is Attenuated by Alcohol Consumption

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a complex clinical problem with significant societal and individual consequences. Up to date it has not been possible to clearly define molecular targets in order to treat MASLD in a comprehensive manner. The role of necroptosis in the pathogenesis of MASLD remains a topic of debate. Previous studies have yielded contradictory results when the necroptosis executioner, mixed lineage kinase domain-like pseudokinase (MLKL), was deleted in mice fed a high-fat/caloric diet. MLKL-/- mice showed either a complete rescue from diet-induced obesity, steatosis and liver damage or no protection at all. We show here, that MLKLK219R knock in mice, which are unable to execute necroptosis, despite the continued expression of the full-length protein, exhibit a protection from Western diet-induced MASLD. As such, they showed reduced weight gain, attenuated steatosis, reduced hepatitis and an increased glucose tolerance. Moreover, MLKLK219R mice showed decreased fat depots, but the lipid metabolism showed no differences compared to WT mice. In line, in vitro experiments revealed impaired differentiation and lipid storage of primary adipocytes isolated from inguinal white adipose tissue (iWAT) from MLKLK219R mice. Interestingly, the additional alcohol consumption, which represents an additional cardiometabolic risk factor for MASLD, partially attenuated the protective effects seen in the dietary model alone. MLKLK219R mice still showed differences in terms of body weight gain, steatosis, hepatitis and glucose tolerance, but liver inflammation was more prevalent.

Together, these results suggest a complex interplay between diet, necroptosis and additional metabolic risk factors in the pathogenesis of MASLD.

Publication History

Article published online:
20 January 2025