Expression of Cytokine Signaling Genes in Morbidly Obese Patients with Non-Alcoholic Steatohepatitis and Hepatic Fibrosis

Background  White adipose tissue (WAT) from visceral adiposity plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Development of NASH and its progression to fibrosis is partially due to cytokines and adipokines produced by WAT. The aim of this study was to assess the association of hepatic fibrosis and NASH by evaluating the intrinsic differences in the inflammatory cytokine signaling in the visceral adipose tissue obtained from morbidly obese patients. Methods  We used targeted microarrays representing human genes involved in the inflammatory and fibrogenic reactions to profile visceral adipose samples of 15 well-matched NASH patients with and without fibrosis. Additionally, visceral adipose samples were subjected to real-time polymerase chain reaction profiling of 84 inflammations related genes. Results  Eight genes (CCL2, CCL4, CCL18, CCR1, IL10RB, IL15RA, and LTB) were differentially expressed in NASH with fibrosis. Additionally, an overlapping but distinct list of the differentially expressed genes were found in NASH with type II diabetes (DM; IL8, BLR1, IL2RA, CD40LG, IL1RN, IL15RA, and CCL4) as compared to NASH without DM. Conclusions  Inflammatory cytokines are differentially expressed in the adipose tissue of NASH with fibrosis, as well in NASH with DM. These findings point at the interaction of adipose inflammatory cytokines, DM, hepatic fibrosis in NASH, and its progression to cirrhosis and end-stage liver disease. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Diagnostic Value of Ultrasonographic Examination for Nonalcoholic Steatohepatitis in Morbidly Obese Patients Undergoing Laparoscopic Bariatric Surgery

Background There are few data relating to the role of fatty score (FS) and modified fatty score (MFS) in ultrasonographic (US) examination on the diagnosis of nonalcoholic steatohepatitis (NASH) in patients undergoing bariatric surgery. Methods We investigated consecutive patients undergoing laparoscopic bariatric surgery with biopsy-proven nonalcoholic fatty liver disease. Patients with other liver diseases and significant alcohol consumption were excluded. Clinico-demographic and anthropometric data were collected before surgery. Each biopsy specimen was assessed by the same pathologist. Liver US examinations were performed by an independent and experienced sonographer before surgery. FS and MFS, determined by the US scoring system based on degrees of parenchymal echogenicity, far gain attenuation, gallbladder wall blurring, portal vein wall blurring and hepatic vein blurring, were used to assess the severity of fatty liver. US findings were correlated with histologic results. Results Totally 101 patients were enrolled. The mean BMI of the patients was 44.6 ± 5.4 kg/m². 29 patients (29%) were categorized with simple steatosis and 72 (71%) with NASH. FS and MFS were significantly correlated with the histological steatosis, fibrosis and the presence of NASH (P < 0.001). A receiver operating characteristic curve identified the MFS of 2 as the best cut-off point for the prediction of NASH, yielding measures of sensitivity, specificity, positive predictive value, and accuracy for 72%, 86%, 93% and 76%, respectively. The positive likelihood ratio of 5.24 for MFS approximately doubled the post-test probability of NASH from 30% to 70%. Conclusion FS and MFS on US examination exhibit acceptable sensitivity and high specificity for the detection of the presence of NASH in morbidly obese patients and may aid in the selection of patients for closer follow-up or liver biopsy.     

Liver tissue microbiota in nonalcoholic liver disease: a change in the paradigm of host-bacterial interactions

Nonalcoholic fatty liver disease (NAFLD) pathogenesis is explained by the complex relationship among diet and lifestyle-predisposing factors, the genetic variance of the nuclear and mitochondrial genome, associated phenotypic traits, and the yet not fully explored interactions with epigenetic and other environmental factors, including the microbiome. Despite the wealth of knowledge gained from molecular and genome-wide investigations in patients with NAFLD, the precise mechanisms that explain the variability of the histological phenotypes are not fully understood. Earlier studies of the gut microbiota in patients with NAFLD and nonalcoholic steatohepatitis (NASH) provided clues on the role of the fecal microbiome in the disease pathogenesis. Nevertheless, the composition of the gut microbiota does not fully explain tissue-specific mechanisms associated with the degree of disease severity, including liver inflammation, ballooning of hepatocytes, and fibrosis. The liver acts as a key filtration system of the whole body by receiving blood from the hepatic artery and the portal vein. Therefore, not only microbes would become entrapped in the complex liver anatomy but, more importantly, bacterial derived products that are likely to be potentially powerful stimuli for initiating the inflammatory response. Hence, the study of liver tissue microbiota offers the opportunity of changing the paradigm of host-NAFLD-microbial interactions from a “gut-centric” to a “liver-centric” approach. Here, we highlight the evidence on the role of liver tissue bacterial DNA in the biology of NAFLD and NASH. Besides, we provide evidence of metagenomic findings that can serve as the seed of further hypothesis-raising studies as well as can be leveraged to discover novel therapeutic targets.     

Gene Expression of Leptin, Resistin, and Adiponectin in the White Adipose Tissue of Obese Patients with Non-Alcoholic Fatty Liver Disease and Insulin Resistance

Background: Adipose tissue is an active endocrine organ that secretes a variety of metabolically important substances including adipokines. These factors affect insulin sensitivity and may represent a link between obesity, insulin resistance, type 2 diabetes (DM), and nonalcoholic fatty liver disease (NAFLD). This study uses real-time polymerase chain reaction (PCR) quantification of mRNAs encoding adiponectin, leptin, and resistin on snap-frozen samples of intra-abdominal adipose tissue of morbidly obese patients undergoing bariatric surgery. Methods: Morbidly obese patients undergoing bariatric surgery were studied. Patients were classified into two groups: Group A (with insulin resistance) (N=11; glucose 149.84 ± 40.56 mg/dL; serum insulin 8.28 ± 3.52 μU/mL), and Group B (without insulin resistance) (N=10; glucose 102.2 ± 8.43 mg/dL; serum insulin 3.431 ± 1.162 μU/mL). Results: Adiponectin mRNA in intra-abdominal adipose tissue and serum adiponectin levels were significantly lower in Group A compared to Group B patients (P<0.016 and P<0.03, respectively). Although serum resistin was higher in Group A than in Group B patients (P<0.005), resistin gene expression was not different between the two groups. Finally, for leptin, neither serum level nor gene expression was different between the two groups. Serum adiponectin level was the only predictor of nonalcoholic steatohepatitis (NASH) in this study (P=0.024). Conclusions: Obese patients with insulin resistance have decreased serum adiponectin and increased serum resistin. Additionally, adiponectin gene expression is also decreased in the adipose tissue of these patients. This low level of adiponectin expression may predispose patients to the progressive form of NAFLD or NASH.