Time-restricted feeding downregulates cholesterol biosynthesis program via RORγ-mediated chromatin modification in porcine liver organoids

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Abstract

Background

Time-restricted feeding (TRF) is a dieting strategy based on nutrients availability and diurnal rhythm, shown to improve lipid metabolism efficiency. We have demonstrated previously that retinoic acid-related (RAR) orphan receptor (ROR) γ is the primary transcription factor controlling cholesterol (CHO) biosynthesis program of animals. However, the functional role of RORγ in liver physiology of pigs in response to TRF has not been determined, largely due to the lack of functional models and molecular tools. In the present study, we established porcine liver organoids and subjected them to restricted nutrients supply for 10-h during the light portion of the day.

Results

Our results showed that TRF regimen did not alter hepatocyte physiology, including unchanged cell viability, caspase 3/7 enzyme activity and the gene signature of cell proliferation in porcine liver organoids, compared to the control group ( P > 0.05). Furthermore, we found that TRF downregulated the hepatic CHO biosynthesis program at both mRNA and protein levels, along with the reduced cellular CHO content in porcine liver organoids ( P < 0.05). Using unbiased bioinformatic analysis of a previous ChIP-seq data and ChIP-qPCR validation, we revealed RORγ as the predominant transcription factor that responded to TRF, amongst the 12 targeted nuclear receptors (NRs) ( P < 0.05). This was likely through RORγ direct binding to the MVK gene (encoding mevalonate kinase). Finally, we showed that RORγ agonists and overexpression enhanced the enrichment of co-factor p300, histone marks H3K27ac and H3K4me1/2, as well as RNA polymerase II (Pol-II) at the locus of MVK, in TRF-porcine liver organoids, compared to TRF-vector control ( P < 0.05).

Conclusions

Our findings demonstrate that TRF triggers the RORγ-mediated chromatin remodeling at the locus of CHO biosynthesis genes in porcine liver organoids and further improves lipid metabolism.

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Fast and accurate short read alignment with Burrows–Wheeler transform

Heng Li, Richard Durbin (2009)

Motivation: The enormous amount of short reads generated by the new DNA sequencing technologies call for the development of fast and accurate read alignment programs. A first generation of hash table-based methods has been developed, including MAQ, which is accurate, feature rich and fast enough to align short reads from a single individual. However, MAQ does not support gapped alignment for single-end reads, which makes it unsuitable for alignment of longer reads where indels may occur frequently. The speed of MAQ is also a concern when the alignment is scaled up to the resequencing of hundreds of individuals. Results: We implemented Burrows-Wheeler Alignment tool (BWA), a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps. BWA supports both base space reads, e.g. from Illumina sequencing machines, and color space reads from AB SOLiD machines. Evaluations on both simulated and real data suggest that BWA is ∼10–20× faster than MAQ, while achieving similar accuracy. In addition, BWA outputs alignment in the new standard SAM (Sequence Alignment/Map) format. Variant calling and other downstream analyses after the alignment can be achieved with the open source SAMtools software package. Availability: http://maq.sourceforge.net Contact: rd@sanger.ac.uk

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The global obesity pandemic: shaped by global drivers and local environments

Boyd Swinburn, Gary Sacks, Kevin D. Hall … (2011)

The Lancet, 378(9793), 804-814

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Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.

Megumi Hatori, Christopher Vollmers, Amir Zarrinpar … (2012)

While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes' expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Kexin Zhang: kitty20010606@126.com

Hao Li: 17633532469@163.com

Zimeng Xin: zimengxin1@outlook.com

Yanwei Li: 2873654125@qq.com

Xiaolong Wang: wangxl@yzu.edu.cn

Yun Hu: huyun@yzu.edu.cn

Haoyu Liu: Haoyu.Liu0523@outlook.com

Demin Cai:

ORCID: http://orcid.org/0000-0003-0500-5292

demincai@yzu.edu.cn

Journal

Journal ID (nlm-ta): J Anim Sci Biotechnol

Journal ID (iso-abbrev): J Anim Sci Biotechnol

Title: Journal of Animal Science and Biotechnology

Publisher: BioMed Central (London )

ISSN (Print): 1674-9782

ISSN (Electronic): 2049-1891

Publication date (Electronic): 2 November 2020

Publication date PMC-release: 2 November 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 106

Affiliations

[1 ]GRID grid.268415.c, College of Animal Science and Technology, , Yangzhou University, ; Yangzhou, 225009 PR China

[2 ]GRID grid.268415.c, Institute of Epigenetics and Epigenomics, Yangzhou University, ; Yangzhou, 225009 PR China

Author information

Demin Cai http://orcid.org/0000-0003-0500-5292

Article

Publisher ID: 511

DOI: 10.1186/s40104-020-00511-9

PMC ID: 7604961

PubMed ID: 33292665

SO-VID: 64f8f1af-0868-457a-b299-757edac2863f

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 20 April 2020

Date accepted : 8 September 2020

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ScienceOpen disciplines: Animal science & Zoology

Keywords: cholesterol biosynthesis program,histone modification,pig,porcine liver organoids,rorγ,time-restricted feeding

Data availability:

ScienceOpen disciplines: Animal science & Zoology

Keywords: cholesterol biosynthesis program, histone modification, pig, porcine liver organoids, rorγ, time-restricted feeding

Time-restricted feeding downregulates cholesterol biosynthesis program via RORγ-mediated chromatin modification in porcine liver organoids

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Most cited references 41

Fast and accurate short read alignment with Burrows–Wheeler transform

The global obesity pandemic: shaped by global drivers and local environments

Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet.

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