Loss of hepatic circadian organization in fatty liver syndrome identifies CLOCK as a regulator of lipid homeostasis in laying hens.
- 1State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, Sichuan, PR China.
- 2Department of Basic Veterinary Medicine, Sichuan Agricultural University, Chengdu, Sichuan, PR China.
- 3State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, PR China; Key Laboratory of Livestock and Poultry Multi-omics, Ministry of Agriculture and Rural Affairs, Sichuan Agricultural University, Chengdu, Sichuan, PR China. Electronic address: [email protected].
Abstract
Fatty liver syndrome (FLS) is a major metabolic disorder in laying hens, but how hepatic lipid dysregulation is linked to circadian disruption remains unclear. Here, we investigated the role of circadian regulation in FLS pathogenesis and focused on the core clock gene Clock Circadian Regulator (CLOCK). In a high-fat diet-induced FLS model in Lohmann pink layers, affected birds showed hepatomegaly, hepatic lipid accumulation, elevated serum total cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase, increased hepatic pro-inflammatory gene expression, and reduced interleukin-10 (IL-10) expression. FLS was also accompanied by reduced laying performance, delayed and dispersed oviposition, and altered temporal profiles of reproductive hormones. Time-series liver transcriptomics across six circadian time points showed extensive transcriptional remodeling in FLS, with dysregulated genes enriched mainly in lipid metabolic and circadian pathways. Pathway analyses indicated increased fatty acid biosynthesis together with reduced fatty acid degradation, glycerophospholipid metabolism, and ether lipid metabolism. Rhythmicity analysis further revealed a marked collapse of hepatic circadian organization: the number of rhythmically expressed genes decreased from 1,046 in controls to 81 in FLS, and core clock genes including CLOCK, cryptochrome 2 (CRY2), and basic helix-loop-helix family member e40 (BHLHE40) lost rhythmic expression. Series Test of Cluster analysis, weighted gene co-expression network analysis, and protein-protein interaction analysis consistently placed CLOCK at the center of the circadian regulatory network associated with hepatic metabolic disturbance. Functional assays in primary chicken hepatocytes showed that CLOCK overexpression reduced lipid accumulation, intracellular total cholesterol and triglyceride levels, and expression of lipogenic genes, while increasing peroxisome proliferation-activated receptor alpha (PPARα) expression and altering multiple circadian regulators. In an oleic acid-induced steatosis model, CLOCK overexpression similarly reduced lipid deposition and inflammatory gene expression, while increasing IL-10, nicotinamide phosphoribosyl transferase (NAMPT), and Sirtuin 1 (SIRT1) expression. This study provides mechanistic insight into the circadian basis of FLS and highlights CLOCK as a potential molecular target for the prevention and intervention of metabolic liver disorders in poultry.
Related
- Pan-Cancer Analysis Identifies LUC7L2 as a Prognostic Biomarker and Potential Functional Regulator of Prostate Cancer Progression
- Cancer type-specific profiling of chromatin regulator mutations identifies recurrent and co-occurring gene sets associated with improved survival following immune checkpoint therapy
- High-throughput protein interactome identifies LSD1 as a regulator of SARS-CoV-2 production through lysine demethylation of viral nucleocapsid protein
- CRISPR-Cas9 screen identifies eIF4G2 as a regulator of CD8+ T cell dysfunction
- Long-read RNA sequencing identifies non-coding isoform switching as a regulator of cell fate
BibTeX
@article{zhai2026loss,
title = {{Loss of hepatic circadian organization in fatty liver syndrome identifies CLOCK as a regulator of lipid homeostasis in laying hens.}},
author = {Chencan Zhai and Kunlong Qi and Zheliang Liu and Baolin Tan and Wei Zhu and Liuting Wu and Gang Shu and Yingjie Wang and Xiaoling Zhao},
journal = {Poultry science},
year = {2026},
month = oct,
doi = {10.1016/j.psj.2026.107877},
url = {https://europepmc.org/article/MED/42868854},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Loss of hepatic circadian organization in fatty liver syndrome identifies CLOCK as a regulator of lipid homeostasis in laying hens.
AU - Chencan Zhai
AU - Kunlong Qi
AU - Zheliang Liu
AU - Baolin Tan
AU - Wei Zhu
AU - Liuting Wu
AU - Gang Shu
AU - Yingjie Wang
AU - Xiaoling Zhao
PY - 2026
DA - 2026/10/05
JO - Poultry science
DO - 10.1016/j.psj.2026.107877
UR - https://europepmc.org/article/MED/42868854
AB - Fatty liver syndrome (FLS) is a major metabolic disorder in laying hens, but how hepatic lipid dysregulation is linked to circadian disruption remains unclear. Here, we investigated the role of circadian regulation in FLS pathogenesis and focused on the core clock gene Clock Circadian Regulator (CLOCK). In a high-fat diet-induced FLS model in Lohmann pink layers, affected birds showed hepatomegaly, hepatic lipid accumulation, elevated serum total cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase, increased hepatic pro-inflammatory gene expression, and reduced interleukin-10 (IL-10) expression. FLS was also accompanied by reduced laying performance, delayed and dispersed oviposition, and altered temporal profiles of reproductive hormones. Time-series liver transcriptomics across six circadian time points showed extensive transcriptional remodeling in FLS, with dysregulated genes enriched mainly in lipid metabolic and circadian pathways. Pathway analyses indicated increased fatty acid biosynthesis together with reduced fatty acid degradation, glycerophospholipid metabolism, and ether lipid metabolism. Rhythmicity analysis further revealed a marked collapse of hepatic circadian organization: the number of rhythmically expressed genes decreased from 1,046 in controls to 81 in FLS, and core clock genes including CLOCK, cryptochrome 2 (CRY2), and basic helix-loop-helix family member e40 (BHLHE40) lost rhythmic expression. Series Test of Cluster analysis, weighted gene co-expression network analysis, and protein-protein interaction analysis consistently placed CLOCK at the center of the circadian regulatory network associated with hepatic metabolic disturbance. Functional assays in primary chicken hepatocytes showed that CLOCK overexpression reduced lipid accumulation, intracellular total cholesterol and triglyceride levels, and expression of lipogenic genes, while increasing peroxisome proliferation-activated receptor alpha (PPARα) expression and altering multiple circadian regulators. In an oleic acid-induced steatosis model, CLOCK overexpression similarly reduced lipid deposition and inflammatory gene expression, while increasing IL-10, nicotinamide phosphoribosyl transferase (NAMPT), and Sirtuin 1 (SIRT1) expression. This study provides mechanistic insight into the circadian basis of FLS and highlights CLOCK as a potential molecular target for the prevention and intervention of metabolic liver disorders in poultry.
SN - 0032-5791
SN - 1525-3171
ER -