Persistent mTORC1 activation underlies sex dimorphic progression of MASLD in mice with hepatocyte prohibitin-1 deficiency.

Prohibitins (PHB1,2) are highly conserved lipid-raft associated proteins that physically interact to form a multimeric ring supercomplex in mitochondrial and plasma membranes where they are intimately involved in regulating cellular metabolism. Prior studies in disparate cell models have implicated PHB1 as a mediator of insulin signaling and its downstream effector, the mechanistic target of rapamycin complex 1 (mTORC1), but the mechanisms and physiological implications of these interactions are unclear. Here, we examined the role of PHB1 in regulating insulin and nutrient mediated activation of mTORC1 in liver using genetic and pharmacological approaches in mice and hepatocyte culture. Interestingly, male mice with hepatocyte-specific PHB1 haploinsufficiency (hPHB1-KD) at 6 months displayed features consistent with metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by liver steatosis and impaired glucose tolerance with hyperinsulinemia, while these parameters were unaffected or even mildly improved in age-matched hPHB1-KD females. Both sexes of hPHB1-KD mice displayed increased basal phosphorylation of mTORC1 and its downstream targets (S6, 4EBP1) in liver compared with WT in fasted state, with minimal responsiveness to insulin. Transcriptomic data revealed strong upregulation of