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A novel experimental model of MetALD in male mice recapitulates key…

- - - - hepatitis B
      - hepatitis C
      - obesity
      - metabolic syndrome
        
        Epidemiological studies have shown a strong causal relationship between alcohol use and metabolic dysfunction–associated steatotic liver disease (MASLD) or metabolic dysfunction–associated steatohepatitis (MASH)
        
        a study in the Japanese population reported that
        
        high alcohol consumption (>40 g/d) in the obese population leads to an almost 2–12 times higher risk of hepatocarcinogenesis than in the nonobese subjects
        
        The coexistence of MASLD and ALD has recently been acknowledged in a separate category of steatotic liver disease known as MetALD
      - diabetes
  - - - progress to fibrosis and early HCC by 48 weeks
        
        closely mimicking the progression of human MASLD and MASH
        
        In this study, we used the high fat-cholesterol-sugar diet, (MASH diet), in combination with alcohol administration for 3 months
        
        increased liver damage
        
        serum bilirubin
        
        decreased liver synthetic function
        
        increased immune cell infiltration
        
        robust inflammation in the liver
        
        increase in epithelial-to-mesenchymal transition (EMT) markers
        
        which correlated with increased fibrosis
- - - - mice received a MASH diet for 3 months with or without chronic alcohol
        
        plus weekly alcohol binges
        
        Survival was >85% in MetALD mice that received alcohol plus MASH diet and 100% in chow, alcohol, and MASH-alone groups
        
        MASH diet–fed mice showed a significant increase in their body weight, as compared to chow-fed mice
        
        Alcohol consumption in MetALD mice and alcohol-alone–fed mice was comparable
        
        blood alcohol levels in MetALD mice were significantly higher compared to alcohol-fed mice
        
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  - - - significant increase in triglyceride levels in mice fed on the MASH diet
        
        significant increase in the level of circulating free fatty acids and total cholesterol in MetALD mice as compared to MASH diet mice
        
        Oil-Red-O staining, which showed an increase in the MetALD mice
        
        MetALD mice displayed a modest increase in fasting glucose as compared to chow mice
        
        qRT-PCR
        
        Fabp4
        
        Fgf21
        
        Plin2
        
        Cpt1a, Cpt1b
        
        Cd36
        
        Lpl
        
        fatty acid synthetase
        
        Sterol regulatory element binding proteins (Srebf1)
        
        CCAAT enhancer binding protein alpha (Cebpa)
        
        diglyceride acyltransferase (DGAT) 1 and 2
  - - - inflammation
        
        IL-1β
        
        interleukin-10 (Il10)
        
        IL-6
      - immune cell infiltration
        
        Monocyte chemoattractant protein-1 (MCP-1)
        
        evaluated the number of activated hepatic macrophages by CD68 immunohistochemistry
        
        Cd163 which was significantly higher in MetALD mice as compared to MASH or alcohol-alone controls
        
        Cd86, another macrophage activation marker
    - - neutrophil infiltration
        
        significant increase in the hepatic expression of neutrophil chemokines such as Cxcl1 and Cxcl2 in MetALD mice
        
        granulocyte chemotactic protein 2 (GCP-2/Cxcl5) was significantly increased in MetALD
        
        mRNA expression of C-X-C Motif Chemokine Receptor 1 (Cxcr1) significantly increased
        
        significant increase in the expression of neutrophil markers, CD11b (Itgam) mRNA
  - - - Severe AH is characterized by fibrosis which also increases the risk of progression to HCC.
        
        Sirius red staining
        
        qRT-PCR
        
        procollagen1α (Col1a1), TGF-β (Tgfb), and tissue inhibitor of matrix metalloproteinases-1 (Timp1)
        
        Alpha-smooth muscle actin (Acta2)
      - EMT
        
        epithelial markers including occludin (Ocln) and claudin (Cldn1) were similarly downregulated in alcohol, MASH, and MetALD mice
        
        mesenchymal markers such as Vimentin (Vim), Col1a1, and Tgfb were significantly increased in MetALD as compared to MASH or alcohol-alone mice
        
        Vimentin protein levels were also significantly higher
  - - - assessed apoptosis
        
        increase in TUNEL + cells in the liver of MetALD mice as compared to any other group
        
        investigated hepatocyte proliferation
        
        level of Ki67, a marker of proliferating cells, was significantly increased in MetALD mice as compared to all other groups both at the mRNA and protein levels
        
        Immunostaining for CK19 in liver sections
      - Hedgehog (Hh) signaling
        
        Hedgehog (Hh) signaling is upregulated in patients with MASH and it positively correlates with the severity of liver disease
        
        Gli1/2/3
    - - vWF levels were measured from serum by ELISA
        
        qRT-PCR