Biology subjects

Gawrieh, S.

Publications and source records attributed to Gawrieh, S..

2 recordsLinked to original sources

bioRxiv2022

Comparative Analysis of Global Hepatic Gene Expression in Adolescents and Adults with Non-alcoholic Fatty Liver Disease

IntroductionTo gain insights into the mechanisms underlying distinct nonalcoholic fatty liver disease (NAFLD) histological phenotypes between children and adults, we compared hepatic gene expression profiles associated with NAFLD phenotypes between the two age groups. MethodsHistological characteristics of intra-operative liver biopsies from adolescents and adults undergoing bariatric surgery were assessed by the same pathologist using the non-alcoholic steatohepatitis (NASH) Clinical Research Network scoring system. Hepatic gene expression was measured by microarray analysis. Transcriptomic signatures of histological phenotypes between the two groups were compared, with significance defined as p-value <0.05 and a fold change >1.5. ResultsIn 67 adolescents and 76 adults, distribution of histological phenotypes was: not-NAFLD (controls) 51% vs 39%, NAFL 39% vs 37%, and NASH 10% vs 24%, respectively. There were 279 differentially expressed genes in adolescents and 213 in adults with NAFLD vs controls. In adolescents, transcriptomes for NAFL vs controls, and borderline vs definite NASH were undifferentiable, whereas in adults, NAFL and borderline NASH demonstrated a transcriptomic gradient between controls and definite NASH. When applied to adolescents, significant adult genes discriminated borderline and definite NASH from control and NAFL, but the majority of significant pediatric genes were not portable to adults. Genes associated with NASH in adolescents and adults showed some ontological consistency but notable differences. ConclusionsThere is some similarity but major differences in the transcriptomic profiles associated with NAFLD between adolescents and adults with severe obesity. These data suggest different mechanisms contribute to the pathogenesis of NAFLD severity at different stages in life. Study HighlightsO_ST_ABSWHAT IS KNOWNC_ST_ABSO_LINonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children and adults C_LIO_LINAFLD histological features and severity differ between children and adults but reasons for these differences are not clear. C_LI WHAT IS NEW HEREO_LIComparison of hepatic gene expression profiles between adolescents and adults with severe obesity and NAFLD showed some similarities but major differences in expressed genes C_LIO_LIThe findings suggest the mechanisms driving different NAFLD severity and phenotypes are different at different stages in life. C_LI

genetics↗

bioRxiv2021

GDF8 Contributes to the Adverse Effects of Liver Injury on Skeletal Muscle Homeostasis and Regeneration

BackgroundAn emerging clinical phenomenon in patients with end stage liver disease is progressive skeletal muscle atrophy. This loss in lean mass predicts poor survival outcomes for liver disease patients and highlights an underappreciated crosstalk between injured liver and muscle that lacks defined mediators. The purpose of our study was to identify potential liver-muscle mediator(s) in pre-clinical in vivo models of liver injury which may contribute to the muscle loss observed in liver disease. MethodsUtilizing a mouse model of carbon tetrachloride CCl4-induced liver injury in the presence or absence of cardiotoxin-induced muscle injury, we evaluated whether neutralizing Activin type IIB receptor (ActRIIB) ligands, or specifically growth differentiation factor 8 (Gdf8), could preserve or reverse muscle atrophy associated with liver disease. ResultsWe found that hepatic injury via CCl4 or bile duct ligation (BDL) similarly caused significant muscle atrophy along with decreased gene expression in key myogenesis markers. This adverse effect of injured liver on muscle were completely prevented and reversed by the intervention of Activin type IIB receptor (ActRIIB)-Fc fusion protein, which neutralizes the ActRIIB ligands, including Activins and growth differentiation factor 8 (Gdf8 or myostatin). The results indicate that ActRIIB ligands promoted muscle atrophy which was manifested in response to hepatic injury/disease and conferred the negative communication of injured liver with muscle. Indeed, direct injection of exogenous Gdf8 protein into muscle along with acute focal muscle injury recapitulated similar dysregulated muscle regeneration as observed with liver injury. Furthermore, we found that hepatocytes produced Gdf8 in response to liver injury in rodents and in patients with end stage liver disease. A neutralizing antibody to Gdf8 attenuated muscle atrophy and unexpectedly ameliorated liver fibrosis in both CCl4 and BDL models. Following this observation, we demonstrated Gdf8s ability to induce fibrogenesis in stellate cells, potentially identifying a novel hepatic role for this protein. Moreover, hepatic Gdf8 promoted muscle wasting in response to liver damage and hindered skeletal muscle regeneration. ConclusionOur findings identified Gdf8 as a novel hepatomyokine contributing to injured liver-muscle negative crosstalk and liver injury progression. Moreover, we demonstrated a promising therapeutic strategy for muscle atrophy accompanying liver diseases.

pathology↗