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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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Dogs with IMHA are predisposed to thrombosis, particularly in pulmonary arteries (Carr et al 2002, DeLaforcade et al 2019), and hypoxic injury to tissues may contribute to hyperlactatemia and organ injury evident in many patients (MacNeill et al 2019)