Nherf2 is a major determinant of bile acid pool dynamics and contributes to regulation of Western diet-induced obesity.

Dysregulation of cholesterol metabolism can lead to obesity and increase the risk of developing many diseases, including type 2 diabetes and cardiovascular diseases. Our previous studies have identified postsynaptic density-95, disc large, and zonula occludens-1 (PDZ) adaptor proteins Na+/H+ exchange regulatory factor Nherf1 (encoded by Nherf1) and Nherf2 (encoded by Nherf2) to be potential regulators of cholesterol metabolism in vitro. In this study, we explored their physiological regulatory function in vivo by using Nherf1- and Nherf2-deficient (Nherf1-/- and Nherf2-/-), and wild-type (C57BL/6) mice. All mice were fed either a chow diet or a cholesterol-enriched Western diet (42% fat, 0.2% cholesterol) for 8 wk starting at 8-wk-old. Our results demonstrate that Nherf2-/-, but not Nherf1-/-, mice are resistant to diet-induced obesity. In Nherf2-/- mice, serum high-density lipoprotein and low-density lipoprotein/very low-density lipoprotein decreased substantially without affecting lipolysis or steroid hormone levels. In addition, distended gallbladders were observed in Nherf2-/- mice, with reduced bile acid output into the intestine and feces, which correlated with decreased cholesterol reabsorption. This led to attenuated Fxr/Shp signaling in the liver and derepressing Cyp7a1 transcription in the absence of Nherf2. These findings suggest a potential role of in regulating gallbladder emptying and lipid homeostasis, offering new insights into potential therapeutic targets for treating diet-induced obesity.NEW & NOTEWORTHY Nherf2-/- but not Nherf1-/- mice demonstrate a resistance to diet-induced obesity. Notably, male Nherf2-/- mice exhibit impaired glucose tolerance and insulin responsiveness, yet neither sex shows further worsening with diet challenge. In addition, elevated hepatic Cyp7a1 levels were observed in Nherf2-/- mice, but there was reduced cholesterol absorption in the ileum, along with enlarged gallbladders and diminished ileal bile acid content, highlighting significant metabolic alterations linked to Nherf2 deficiency.