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Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic…
Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans
Introduction
alcoholic liver disease
including steatosis, steatohepatitis (ASH), cirrhosis, and hepatocellular carcinoma
Alcoholic hepatitis associated with high mortality
The typical histology findings in AH patients show severe ASH, including steatosis, hepatocyte ballooning, neutrophilic infiltration, Mallory-Denk hyaline inclusions, and chicken wire fibrosis.
the pathogenesis of AH remains obscure
little progress has been made in the management of severe AH
Slow progress in the field of ALD has resulted partly from a lack of experimental models of advanced ALD and a lack of comparative translational studies
the pathogenesis of AH
developed an integrative approach by comparing transcriptome data from this clinically relevant model and biopsy-proven ASH from AH patients, and we identified many genes that were similarly dysregulated in the animal model and in AH samples.
FSP27 was found to be highly expressed in adipose tissues and to function as a lipid droplet-binding protein that promotes lipid accumulation in adipocytes.
Results
Chronic-Plus-Binge Ethanol Feeding Induces More Severe ASH Than Short-term–Plus–Binge Feeding in Mice
evaluated the liver injury in male C57BL/6N mice fed ethanol for 10 days- to 12 weeks-plus-one binge
H&E staining
serum ALT and AST from different feeding models
neutrophils
hepatic triglyceride levels
liver fibrosis (as determined by α-smooth muscle actin [SMA] staining, Sirus red staining, expression of collagens)
the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling-positive (TUNEL+) hepatocytes
Cxcl4, Icam-1, Tnfα, IL-1β, and Ly6G expression
Chronic-Plus-Binge Ethanol Feeding Up-Regulates Expression of Hepatic Genes Fsp27α and Fsp27β in Mice in a PPARγ- and CREBH-Dependent Manner, Respectively
Mice from different feeding models were used
Real-time PCR analyses of liver tissue
Western blot analyses of liver tissues
expression of PPARγ and active nuclear form of CREBH-N protein
Inhibition of the Fsp27 Gene Expression by Injection of Ad-Fsp27shRNA or by Genetic Disruption Ameliorates Chronic-Plus-Binge Ethanol-Induced ASH
Mice were fed E8w+1B and administered Ad-control-shRNA or Ad-shFsp27 for the final 5 days.
Real-time PCR analyses
Fsp27Hep−/− and WT mice
treatment of mice with the PPARγ inhibitor GW9662 or knockdown of Crebh by administration of Ad-shCREBH
serum ALT and AST levels
representative H&E staining