Journal Article

Spatial Transcriptomic Study Reveals Heterogeneous Metabolic Adaptation and a Role of Pericentral PPARα/CAR/Ces2a Axis During Fasting in Mouse Liver

Zhang, Tingguo, Feng, Yawei, Mi, Ping, Liang, Jinyuan, Liu, Zhiping, Zhang, Yi, Han, Penghu, Yuan, Detian, Li, Shiyang, Li, Xinying, Zhang, Cuijuan, Xu, Bowen, Shen, Jing, Zheng, Mengqi, Wang, Shiguan

2024

Overview

Spatial heterogeneity and plasticity of the mammalian liver are critical for systemic metabolic homeostasis in response to fluctuating nutritional conditions. Here, a spatially resolved transcriptomic landscape of mouse livers across fed, fasted and refed states using spatial transcriptomics is generated. This approach elucidated dynamic temporal‐spatial gene cascades and how liver zonation—both expression levels and patterns—adapts to shifts in nutritional status. Importantly, the pericentral nuclear receptor Nr1i3 (CAR) as a pivotal regulator of triglyceride metabolism is pinpointed. It is showed that the activation of CAR in the pericentral region is transcriptionally governed by Pparα. During fasting, CAR activation enhances lipolysis by upregulating carboxylesterase 2a, playing a crucial role in maintaining triglyceride homeostasis. These findings lay the foundation for future mechanistic studies of liver metabolic heterogeneity and plasticity in response to nutritional status changes, offering insights into the zonated pathology that emerge during liver disease progression linked to nutritional imbalances. Spatial transcriptomics reveals how mouse liver zonation adapts to nutritional changes, highlighting the pericentral nuclear receptor CAR as a key regulator of triglyceride metabolism. CAR activation, transcriptionally governed by PPARα, enhances lipolysis during fasting by upregulating carboxylesterase 2a, crucial for maintaining triglyceride homeostasis. This study provides insights into the liver's metabolic heterogeneity and plasticity.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Adaptation, Physiological - genetics / Animals / Biosynthesis / Carboxylic Ester Hydrolases - genetics / Carboxylic Ester Hydrolases - metabolism / Cholesterol / constitutive androstane receptor (CAR) / Constitutive Androstane Receptor - metabolism / Enzymes / Fasting / Fasting - metabolism / fasting response / Fatty acids / Gene expression / Gene Expression Profiling - methods / Homeostasis / Liver / Liver - metabolism / liver zonation / Male / metabolic heterogeneity / Metabolism / Mice / Mice, Inbred C57BL / peroxisome proliferator‐activated receptor alpha (Pparα) / Physiology / PPAR alpha - genetics / PPAR alpha - metabolism / spatial transcriptomics / Steroids / Transcriptome - genetics