ABSTRACT
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with visceral adiposity. The secretion of adipocytokines from white adipose tissue (WAT) promoting necroinflammation, and/or fibrosis may play important roles in the pathogenesis of non-alcoholic steatohepatits (NASH). In a previous study, reduced expression of a number of miRNA species in WAT concomitant with histological diagnosis of NASH was successfully demonstrated. In this study, we measure the expression of several predicted miRNA regulatory targets relevant to NAFLD and NASH including mTOR, FAS, IL20, SEMA4C, ADAMTS6 and IL13RA. We then examine hepatic receptor expression by immunohistochemical staining and qPCR. METHODS: White adipose tissue was collected from 24 obese patients undergoing bariatric surgery with biopsy-proven NAFLD. Extracted total RNAs from the adipose tissue were reverse transcribed and profiled for gene expression by qPCR for specific individual mRNA targets defined after identification by any two of three of the major prediction services: miRanda, TarBase or PicTar. All liver biopsies were read by a singly hepatopathologist. The same liver tissue was used to stain for hepatic receptor expression for FASLG and IL20. Additionally, the same tissue was used for qPCR for FASLG and IL20. RESULTS: Increases in the expression of IL13RA, mTOR, IL20, SEMA4C and FAS were detected and negatively correlated with putative regulatory miRNA. Hepatic receptor expression for FAS and IL20 was noted to correlate with markers of inflammation and severity of NAFLD. CONCLUSION: These data are consistent with the hypothesis that specific adipocytokines secreted by WAT will impact hepatic tissue and participate in the pathogenesis of NASH.
Subject(s)
Adipokines/genetics , Adipose Tissue, White/chemistry , Liver/chemistry , MicroRNAs/genetics , Non-alcoholic Fatty Liver Disease/genetics , Obesity/genetics , Adult , Biopsy , Case-Control Studies , Female , Gene Expression Regulation , Gene Regulatory Networks , Humans , Inflammation Mediators/analysis , Liver/pathology , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/diagnosis , Obesity/complications , Obesity/diagnosis , Paracrine Communication , RNA, Messenger/genetics , Receptors, Interleukin/genetics , Reverse Transcriptase Polymerase Chain Reaction , Severity of Illness Index , Signal Transduction , fas Receptor/geneticsABSTRACT
BACKGROUND AND AIM: Recently, microRNAs (miRNA) have been linked to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH). First transcribed as pri-miRNA, these molecules are further processed by a complex of endonuclear and cytosolic RNA binding molecules to form mature miRNAs. The aim of this study is to investigate mechanisms of miRNA regulation in the visceral adipose of obese NAFLD patients via measuring expression of miRNA processing enzymes and pri-miRNA. METHODS: Total RNAs were extracted from visceral adipose tissue (VAT) samples collected from patients undergoing bariatric surgery. All patients had biopsy-proven NAFLD (NASH patients [n = 12] and non-NASH NAFLD [n = 12]). For each patient, we profiled mRNA levels for three miRNA processing elements (Drosha, DGCR8, and Dicer1) and seven pri-miRNAs (pri-miR-125b-2, pri-miR-16-2, pri-miR-26a-1, pri-miR-26a-2, pri-miR-7-1, pri-miR-7-2, and pri-miR-7-3). RESULTS: Expression of Dicer1, Drosha and DGCR8 was significantly increased within the NASH cohort along with expression of pri-miR-7-1. The presence of focal necrosis on the liver biopsy correlated significantly with levels of Dicer1 and DGRC8. Both NASH and ballooning degeneration of hepatocytes correlated negatively with the expression levels of hsa-miR-125b. Histologic NASH correlated positively with the expression levels of pri-miR-16-2 and pri-miR-7-1. The presence of the hepatocyte's ballooning degeneration in the liver biopsy correlated positively with pri-miR-26a-1 and pri-miR-7-1. The expression profile of pri-miR-125b-2 also correlated positively with body mass index. CONCLUSIONS: Our findings support the hypothesis that VAT-derived miRNA may contribute to the pathogenesis of NASH in obese patients.
Subject(s)
DEAD-box RNA Helicases/genetics , DEAD-box RNA Helicases/metabolism , Fatty Liver/enzymology , Fatty Liver/genetics , Gene Expression Regulation, Enzymologic/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Proteins/genetics , Proteins/metabolism , Ribonuclease III/genetics , Ribonuclease III/metabolism , Adult , Body Mass Index , Cohort Studies , Disease Progression , Fatty Liver/pathology , Female , Humans , Intra-Abdominal Fat/enzymology , Intra-Abdominal Fat/metabolism , Liver/pathology , Male , Middle Aged , Necrosis , Non-alcoholic Fatty Liver Disease , Obesity , RNA-Binding ProteinsABSTRACT
While several hypotheses have been put forward to explain how prostate tumors become resistant to androgen deprivation therapy, the mechanism by which prostate tumors have increased androgen concentrations as compared to the serum has been poorly explored. Using a stromal/epithelial cell co-culture model, Mizokami et al. have demonstrated how prostate-, bone- and prostate tumor-derived stromal cells participate with tumor-derived epithelial cells (i.e., LNCaP cells) to produce active androgens from a readily available substrate during androgen deprivation therapy, dehydroepiandrosterone (DHEA). Although these experiments are conducted in vitro, they provide a basis for the possibility of intratumoral DHEA-mediated androgen synthesis mechanisms that may underlie androgen receptor reactivation during androgen deprivation in many prostate tumors. Moreover, Mizokami et al. have shown that dutasteride, previously considered an SRD5A inhibitor, also inhibits the interplay between stromal and epithelial cells in the synthesis of testosterone. Herein, we summarize this study and comment on therapeutic implications.
