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Abbreviations ACC: acetyl-coenzyme A carboxylase AKT1: RAC-α serine/threonine-protein kinase ALT: alanine aminotransferase AMPK: AMP-activated protein kinase BAs: bile acids BCAAs: branched-chain amino acids BCFAs: branched-chain fatty acids BMI: body mass index CCK: cholecystokinin CCL2: C-C motif chemokine ligand 2 CCR2: C-C motif chemokine receptor 2 CKD: chronic kidney disease CMAs: combined metabolic activators CoA: coenzyme A CVD: cardiovascular disease CXCL8: C-X-C motif chemokine ligand 8 DNL: de novo lipogenesis DR: ductular reaction FAS: fatty acid synthase FFAs: free fatty acids FGFs: fibroblast growth factors FXR: farnesoid X receptor GLP-1: glucagon-like peptide-1 GPCRs: G protein-coupled receptors HCC: hepatocellular carcinoma HFD: high-fat diet HIF-1α: hypoxia-inducible factor-1α HSCs: hepatic stellate cells IL: interleukin KCs: Kupffer cells LDL-c: low-density lipoprotein cholesterol LFD: low-fat diet LPSs: lipopolysaccharides LSEC: liver sinusoidal endothelial cell NAFLD: non-alcoholic fatty liver disease NASH: non-alcoholic steatohepatitis NF-κB: nuclear factor-κB NK: natural killer NKT: natural killer T NLR: neutrophil-to-lymphocyte ratio NLRP3: NOD-like receptor family pyrin domain-containing 3 Nrf2: nuclear factor erythroid 2-related factor 2 PA: palmitic acid PPARγ: peroxisome proliferator-activated receptor γ SCFAs: short-chain fatty acids SGLT2: sodium-glucose co-transporter 2 SREBP-1c: sterol regulatory element-binding protein-1c T2DM: type 2 diabetes mellitus TG: triglyceride TMAO: trimethylamine N -oxide TNF: tumor necrosis factor TNFR2: tumor necrosis factor receptor 2 Declarations Author contributions CZ: Conceptualization, Investigation, Writing—original draft, Writing—review & editing

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doi: 10.1038/s41581-021-00487-3 83 SilverSABeaubien-SoulignyWShahPSHarelSBlumDKishibeTet al