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 <i>Nherf1</i>) and Nherf2 (encoded by <i>Nherf2</i>) 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 (<i>Nherf1</i>^-/- and <i>Nherf2</i>^-/-), 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 <i>Nherf2</i>^-/-, but not <i>Nherf1</i>^-/-, mice are resistant to diet-induced obesity. In <i>Nherf2</i>^-/- 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 <i>Nherf2</i>^-/- 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 <i>Cyp7a1</i> 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.<b>NEW & NOTEWORTHY</b> <i>Nherf2</i>^-/- but not <i>Nherf1</i>^-/- mice demonstrate a resistance to diet-induced obesity. Notably, male <i>Nherf2</i>^-/- mice exhibit impaired glucose tolerance and insulin responsiveness, yet neither sex shows further worsening with diet challenge. In addition, elevated hepatic <i>Cyp7a1</i> levels were observed in <i>Nherf2</i>^-/- 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.