A high fat, high sugar diet induces hepatic Peroxisome proliferator-activated receptor gamma coactivator 1-alpha promoter hypermethylation in male Wistar rats

Yoonus Abrahams; Tarryn Willmer; Oelfah Patel; Ebrahim Samodien; Christo J F Muller; Shantal Windvogel; Rabia Johnson; Carmen Pheiffer

doi:10.1016/j.bbrc.2023.09.004

A high fat, high sugar diet induces hepatic Peroxisome proliferator-activated receptor gamma coactivator 1-alpha promoter hypermethylation in male Wistar rats

Biochem Biophys Res Commun. 2023 Nov 5:680:25-33. doi: 10.1016/j.bbrc.2023.09.004. Epub 2023 Sep 7.

Authors

Yoonus Abrahams¹, Tarryn Willmer², Oelfah Patel³, Ebrahim Samodien⁴, Christo J F Muller⁵, Shantal Windvogel⁶, Rabia Johnson¹, Carmen Pheiffer⁷

Affiliations

¹ Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
² Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
³ Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Division of Clinical Pharmacology, Department of Medicine, Faculty of Medicine and Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
⁴ Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa.
⁵ Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa, South Africa.
⁶ Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
⁷ Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg, South Africa; Centre for Cardio-Metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa; Department of Obstetrics and Gynaecology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa. Electronic address: carmen.pheiffer@mrc.ac.za.

PMID: 37713959
DOI: 10.1016/j.bbrc.2023.09.004

Abstract

Previously we reported that a high fat, high sugar (HFHS) diet induced adiposity, hyperinsulinaemia, hyperleptinaemia, hypertriglyceridaemia and increased liver mass in male Wistar rats. In the present study, the mechanisms underlying the increased liver mass were further elucidated by assessing hepatic lipid accumulation and the expression and methylation status of key metabolic genes using histology, quantitative real-time PCR and pyrosequencing, respectively. The HFHS diet induced hepatic steatosis, increased hepatic triglycerides (1.8-fold, p < 0.001), and increased the expression of sterol regulatory element-binding transcription factor 1 (Srebf1) (2.0-fold, p < 0.001) and peroxisome proliferator-activated receptor gamma (Pparg) (1.7-fold, p = 0.017) in the liver. The expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc1a) was decreased (2.6-fold, p < 0.010), which was accompanied by hypermethylation (p = 0.018) of a conserved CpG site in the promoter of Pgc1a in HFHS fed rats compared to controls. In silico analysis identified putative binding sites for CCAAT/enhancer-binding protein beta (C/EBPß) and hepatocyte nuclear factor 1 (HNF1) within proximity to the hypermethylated CpG. As Pgc1a is a co-activator of several transcription factors regulating multiple metabolic pathways, hypermethylation of this conserved CpG site in the promoter of Pgc1a may be one possible mechanism contributing to the development of hepatic steatosis in response to a HFHS diet. However, further work is required to confirm the role of Pgc1a in steatosis.

Keywords: DNA methylation; Liver; Peroxisome proliferator-activated receptor gamma; Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; Steatosis; Sterol regulatory element-binding transcription factor 1.