Male cholesterol metabolism appears more responsive to gut-brain signaling disruption than previously recognized, with potential implications for personalized cardiovascular interventions. This mechanistic insight challenges the assumption that short-chain fatty acid receptors function uniformly across sexes in metabolic regulation.
Genetic deletion of the GPR41 receptor in male mice produced striking reductions in LDL cholesterol, triglycerides, and abdominal fat accumulation compared to normal littermates. The knockout animals showed elevated cecal propionate concentrations alongside diminished expression of Npc1l1, a critical intestinal cholesterol transporter. Simultaneously, their gut microbiome composition shifted significantly, accompanied by reduced microbially-derived bile acid levels and enhanced intestinal motility patterns.
This research illuminates a previously underappreciated sex-specific pathway linking fiber fermentation byproducts to lipid homeostasis. GPR41 normally responds to propionate and butyrate from dietary fiber breakdown, but its absence paradoxically improved several cardiovascular risk markers in males while leaving atherosclerotic plaque formation unchanged. The findings suggest GPR41 may function as a metabolic brake on propionate accumulation rather than simply a beneficial SCFA sensor. Notably, female mice showed no comparable responses, indicating hormonal or genetic factors modulate this receptor's metabolic influence. While these mouse model results require human validation, they point toward GPR41 as a potential therapeutic target for male-specific cholesterol management strategies, particularly those incorporating microbiome modulation through targeted dietary fiber interventions.
