Hyperlipidemia May Synergize with Hypomethylation in Establishing Trained Immunity and Promoting Inflammation in NASH and NAFLD.

Abstract

We performed a panoramic analysis on both human nonalcoholic steatohepatitis (NASH) microarray data and microarray/RNA-seq data from various mouse models of nonalcoholic fatty liver disease NASH/NAFLD with total 4249 genes examined and made the following findings: (i) human NASH and NAFLD mouse models upregulate both cytokines and chemokines; (ii) pathway analysis indicated that human NASH can be classified into metabolic and immune NASH; methionine- and choline-deficient (MCD)+high-fat diet (HFD), glycine N-methyltransferase deficient (GNMT-KO), methionine adenosyltransferase 1A deficient (MAT1A-KO), and HFCD (high-fat-cholesterol diet) can be classified into inflammatory, SAM accumulation, cholesterol/mevalonate, and LXR/RXR-fatty acid β-oxidation NAFLD, respectively; (iii) canonical and noncanonical inflammasomes play differential roles in the pathogenesis of NASH/NAFLD; (iv) trained immunity (TI) enzymes are significantly upregulated in NASH/NAFLD; HFCD upregulates TI enzymes more than cytokines, chemokines, and inflammasome regulators; (v) the MCD+HFD is a model with the upregulation of proinflammatory cytokines and canonical and noncanonical inflammasomes; however, the HFCD is a model with upregulation of TI enzymes and lipid peroxidation enzymes; and (vi) caspase-11 and caspase-1 act as upstream master regulators, which partially upregulate the expressions of cytokines, chemokines, canonical and noncanonical inflammasome pathway regulators, TI enzymes, and lipid peroxidation enzymes. Our findings provide novel insights on the synergies between hyperlipidemia and hypomethylation in establishing TI and promoting inflammation in NASH and NAFLD progression and novel targets for future therapeutic interventions for NASH and NAFLD, metabolic diseases, transplantation, and cancers.

• Authors: Charles I V Drummer, Fatma Saaoud, Yu Sun, Diana Atar, Keman Xu, Yifan Lu, Ying Shao, Candice Johnson, Lu Liu, Huimin Shen, Nirag C Jhala, Xiaohua Jiang, Hong Wang, Xiaofeng Yang
• Journal: Journal of immunology research (J Immunol Res) Vol. 2021 Pg. 3928323 ( 2021) ISSN: 2314-7156 [Electronic] Egypt
• PMID: 34859106 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Charles I. V. Drummer et al.

Chemical References

• Cytokines
• Inflammation Mediators
• Glycine N-Methyltransferase
• Mat1a protein, mouse
• Methionine Adenosyltransferase
• Caspases
• caspase 11, human
• Caspase 1

Topics

• Animals
• Caspase 1 (metabolism)
• Caspases (metabolism)
• Cytokines (metabolism)
• Diet, High-Fat
• Disease Models, Animal
• Glycine N-Methyltransferase (genetics)
• Humans
• Hyperlipidemias (immunology)
• Immunity
• Inflammation (immunology)
• Inflammation Mediators (metabolism)
• Methionine Adenosyltransferase (genetics)
• Methylation
• Mice
• Mice, Knockout
• Non-alcoholic Fatty Liver Disease