Loss of metabolic adaptation in lean MAFLD is driven by endotoxemia leading to epigenetic reprogramming

Jawaher Alharthi; Ziyan Pan; Brian S Gloss; Duncan McLeod; Martin Weltman; Jacob George; Mohammed Eslam

doi:10.1016/j.metabol.2023.155583

Loss of metabolic adaptation in lean MAFLD is driven by endotoxemia leading to epigenetic reprogramming

Metabolism. 2023 Jul:144:155583. doi: 10.1016/j.metabol.2023.155583. Epub 2023 May 4.

Authors

Jawaher Alharthi¹, Ziyan Pan², Brian S Gloss³, Duncan McLeod⁴, Martin Weltman⁵, Jacob George², Mohammed Eslam⁶

Affiliations

¹ Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia; Department of Biotechnology, Faculty of Science, Taif University, Taif, Saudi Arabia.
² Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
³ Westmead Research Hub, Westmead Institute for Medical Research, Sydney, NSW, Australia.
⁴ Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, Australia.
⁵ Department of Gastroenterology and Hepatology, Nepean Hospital, Sydney, NSW, Australia.
⁶ Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia. Electronic address: [email protected].

PMID: 37146900
DOI: 10.1016/j.metabol.2023.155583

Abstract

Lean patients with MAFLD have an initial adaptive metabolic response characterised by increased serum bile acids and Farnesoid X Receptor (FXR) activity. How this adaptive response wanes resulting in an equal or perhaps worse long-term adverse outcome compared to patients with obese MAFLD is not known. We show that patients with lean MAFLD have endotoxemia while their macrophages demonstrate excess production of inflammatory cytokines in response to activation by Toll-like receptor (TLR) ligands when compared to healthy subjects. Alterations of the lean MAFLD macrophage epigenome drives this response and suppresses bile acids signalling to drive inflammation. Our data suggests that selectively restoring bile acids signalling might restore adaptive metabolic responses in patients with MAFLD who are lean.

Keywords: Bile acids; Epigenetics; MAFLD; Metabolic adaptation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bile Acids and Salts
Endotoxemia* / genetics
Epigenesis, Genetic
Humans
Inflammation / genetics
Non-alcoholic Fatty Liver Disease*
Receptors, Cytoplasmic and Nuclear / genetics

Substances

Receptors, Cytoplasmic and Nuclear
Bile Acids and Salts