Title
Translational characterization of the temporal dynamics of metabolic dysfunctions in liver, adipose tissue and the gut during diet-induced NASH development in Ldlr-/-.Leiden mice
Author
Gart, E.
van Duyvenvoorde, W.
Snabel, J.
de Ruiter, C.
Attema, J.
Caspers, M.P.M.
Lek, S.
van Heuven, B.J.
Speksnijder, A.G.C.L.
Giera, M.
Menke, A.
Salic, K.
Bence, K.K.
Tesz, G.J.
Keijzer, J.
Kleemann, R.
Morrison, M.C.
Publication year
2023
Abstract
Background: NAFLD progression, from steatosis to inflammation and fibrosis, results from an interplay of intra- and extrahepatic mechanisms. Disease drivers likely include signals from white adipose tissue (WAT) and gut. However, the temporal dynamics of disease development remain poorly understood. Methods: High-fat-diet (HFD)-fed Ldlr-/-.Leiden mice were compared to chow-fed controls. At t = 0, 8, 16, 28 and 38w mice were euthanized, and liver, WAT depots and gut were analyzed biochemically, histologically and by lipidomics and transcriptomics together with circulating factors to investigate the sequence of pathogenic events and organ cross-talk during NAFLD development. Results: HFD-induced obesity was associated with an increase in visceral fat, plasma lipids and hyperinsulinemia at t = 8w, along with increased liver steatosis and circulating liver damage biomarkers. In parallel, upstream regulator analysis predicted that lipid catabolism regulators were deactivated and lipid synthesis regulators were activated. Subsequently, hepatocyte hypertrophy, oxidative stress and hepatic inflammation developed. Hepatic collagen accumulated from t = 16 w and became pronounced at t = 28-38 w. Epididymal WAT was maximally hypertrophic from t = 8 w, which coincided with inflammation development. Mesenteric and subcutaneous WAT hypertrophy developed slower and did not appear to reach a maximum, with minimal inflammation. In gut, HFD significantly increased permeability, induced a shift in microbiota composition from t = 8 w and changed circulating gut-derived metabolites. Conclusion: HFD-fed Ldlr-/-.Leiden mice develop obesity, dyslipidemia and insulin resistance, essentially as observed in obese NAFLD patients, underlining their translational value. We demonstrate that marked epididymal-WAT inflammation, and gut permeability and dysbiosis precede the development of NAFLD stressing the importance of a multiple-organ approach in the prevention and treatment of NAFLD.
Subject
Inter-organ crosstalk
Liver fibrosis
Non-alcoholic fatty liver disease
Oxidative stress
Temporal dynamics
To reference this document use:
http://resolver.tudelft.nl/uuid:4ba96c85-d000-4453-85df-b78526e15f77
DOI
https://doi.org/10.1016/j.heliyon.2023.e13985
TNO identifier
984433
Source
Heliyon, 9 (9)
Document type
article