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.
Highlights
Several metabolic diseases significantly drive the development of cardiovascular disease, nonalcoholic fatty liver disease (NAFLD) [1], and nonalcoholic steatohepatitis (NASH) [2]
Our results have demonstrated innate immune secretomic cytokines and chemokines suggesting that human NASH and NAFLD mouse models share innate immune mechanisms and there is a significant role of exosomes and caspase-4 secretomic in driving liver and systemic inflammations
The results showed that the atorvastatin treatment overlapped with 13 trained immunity (TI) enzyme genes upregulated in human and mouse NASH/NAFLD models
Summary
Several metabolic diseases significantly drive the development of cardiovascular disease, nonalcoholic fatty liver disease (NAFLD) [1], and nonalcoholic steatohepatitis (NASH) [2]. NASH is characterized by macrovascular steatosis, hepatocellular ballooning, lobular inflammation, and pericellular fibrosis. NAFLD constitutes a major health concern, and NAFLD prevalence is estimated between 25% and 30% in the general population [3]. The exact underlying inflammatory mechanisms that trigger the transition from fatty liver to NASH remain unclear. Innate immune system inflammation is considered a landmark of NASH pathogenesis.
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