Browsing by Subject "Non-alcoholic Fatty Liver Disease"

Now showing 1 - 5 of 5
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    Circulating cell-free messenger RNA secretome characterization of primary sclerosing cholangitis
    (Wolters Kluwer, 2023-05-23) Chalasan, Naga; Vuppalanchi, Raj; Lammert, Craig; Gawrieh, Samer; Braun, Jerome V.; Zhuang, Jiali; Ibarra, Arkaitz; Ross, David A.; Nerenberg, Michael; Quake, Stephen R.; Sninsky, John J.; Toden, Shusuke; Medicine, School of Medicine
    Background: Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by multifocal bile duct strictures. To date, underlying molecular mechanisms of PSC remain unclear, and therapeutic options are limited. Methods: We performed cell-free messenger RNA (cf-mRNA) sequencing to characterize the circulating transcriptome of PSC and noninvasively investigate potentially bioactive signals that are associated with PSC. Serum cf-mRNA profiles were compared among 50 individuals with PSC, 20 healthy controls, and 235 individuals with NAFLD. Tissue and cell type-of-origin genes that are dysregulated in subjects with PSC were evaluated. Subsequently, diagnostic classifiers were developed using PSC dysregulated cf-mRNA genes. Results: Differential expression analysis of the cf-mRNA transcriptomes of PSC and healthy controls resulted in identification of 1407 dysregulated genes. Furthermore, differentially expressed genes between PSC and healthy controls or NAFLD shared common genes known to be involved in liver pathophysiology. In particular, genes from liver- and specific cell type-origin, including hepatocyte, HSCs, and KCs, were highly abundant in cf-mRNA of subjects with PSC. Gene cluster analysis revealed that liver-specific genes dysregulated in PSC form a distinct cluster, which corresponded to a subset of the PSC subject population. Finally, we developed a cf-mRNA diagnostic classifier using liver-specific genes that discriminated PSC from healthy control subjects using gene transcripts of liver origin. Conclusions: Blood-based whole-transcriptome cf-mRNA profiling revealed high abundance of liver-specific genes in sera of subjects with PSC, which may be used to diagnose patients with PSC. We identified several unique cf-mRNA profiles of subjects with PSC. These findings may also have utility for noninvasive molecular stratification of subjects with PSC for pharmacotherapy safety and response studies.
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    In a pilot study, reduced fatty acid desaturase 1 function was associated with nonalcoholic fatty liver disease and response to treatment in children
    (Springer Nature, 2018-11) Nobili, Valerio; Alisi, Anna; Liu, Zhipeng; Liang, Tiebing; Crudele, Annalisa; Raponi, Massimiliano; Lin, Jingmei; Chalasani, Naga P.; Liu, Wanqing; Pathology and Laboratory Medicine, School of Medicine
    BACKGROUND: FADS1 gene encodes delta 5 desaturase, a rate-limiting enzyme in the metabolism of n-3 and n-6 polyunsaturated fatty acids (PUFAs). Minor alleles of FADS1 locus polymorphisms are associated with reduced FADS1 expression and intra-hepatic fat accumulation. However, the relationship between FADS1 expression and pediatric nonalcoholic fatty liver disease (NAFLD) risk remains to be explored. METHODS: We analyzed FADS1 transcription levels and their association with intra-hepatic fat and histology in children, and we performed pathway enrichment analysis on transcriptomic profiles associated with FADS1 polymorphisms. We also evaluated the weight of FADS1 alleles on the response to combined docosahexaenoic acid, choline, and vitamin E (DHA-CHO-VE) treatment. RESULTS: FADS1 mRNA level was significantly and inversely associated with intra-hepatic fat (p = 0.004), degree of steatosis (p = 0.03), fibrosis (p = 0.05), and NASH (p = 0.008) among pediatric livers. Transcriptomics demonstrated a significant enrichment of a number of pathways strongly related to NAFLD (e.g., liver damage, fibrosis, and hepatic stellate cell activation). Compared to children who are common allele homozygotes, children with FADS1 minor alleles had a greater reduction in steatosis, fibrosis, and NAFLD activity score after DHA-CHO-VE. CONCLUSION: This study suggests that decreased FADS1 expression may be associated with NAFLD in children but an increased response to DHA-CHO-VE.
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    Pharmacotherapy for Nonalcoholic Fatty Liver Disease
    (Thieme Publishing Group, 2015-08) Gawrieh, Samer; Chalasani, Naga; Department of Medicine, School of Medicine
    Lifestyle modifications and optimization of the management of cardiometabolic comorbidities are currently the mainstay of treatment for patients with nonalcoholic fatty liver disease. Pharmacotherapy to halt or reverse hepatic histological injury and prevent the development of end-stage liver disease is specifically offered to patients with nonalcoholic steatohepatitis (NASH) and those with advanced fibrosis. In this review, the authors discuss the state of the art of various pharmacological agents for NASH. The efficacy of vitamin E and pioglitazone is reasonably well established in a selected group of patients with NASH. Current data do not offer convincing evidence for efficacy of pentoxifylline, long-chain polyunsaturated fatty acids, angiotensin receptor blockers, metformin, or ursodeoxycholic acid. They also discuss the state of several emerging agents for treating NASH including the farsenoid X receptor ligand, obeticholic acid.
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    Relationship between changes in serum levels of keratin 18 and changes in liver histology in children and adults with nonalcoholic fatty liver disease
    (Elsevier, 2014-12) Vuppalanchi, Raj; Jain, Ajay K.; Deppe, Ross; Yates, Katherine; Comerford, Megan; Masuoka, Howard C.; Neuschwander-Tetri, Brent A.; Loomba, Rohit; Brunt, Elizabeth M.; Kleiner, David E.; Molleston, Jean P.; Schwimmer, Jeffrey B.; Lavine, Joel E.; Tonascia, James; Chalasani, Naga; Department of Medicine, IU School of Medicine
    BACKGROUND & AIMS: Cross-sectional studies have associated serum levels of the keratin 18 (K18) fragment with histologic features of liver in individuals with nonalcoholic fatty liver disease (NAFLD). We investigated the relationship between changes in serum levels of K18 and changes in liver histology in adults and children with NAFLD. METHODS: We measured levels of K18 in stored serum samples collected at baseline and various time points from 231 adults with nonalcoholic steatohepatitis and 152 children with NAFLD who participated in 2 separate prospective randomized clinical trials. Liver biopsy specimens collected at baseline and week 96 were reviewed centrally. RESULTS: There were greater decreases in serum levels of K18 in adults with histologic improvement at week 96 than in those without histologic improvement at week 16 (decrease, 193 ± 293 vs 139 ± 467 U/L; P < .001), week 48 (decrease, 232 ± 360 vs 113 ± 425 U/L; P < .001), or week 96 (decrease, 269 ± 368 vs 97 ± 400 U/L; P < .001). There were greater decreases in serum levels of K18 in children with histologic improvements than in those without histologic improvements at week 48 (decrease, 197 ± 467 vs 47 ± 350 U/L; P = .005) and week 96 (decrease, 206 ± 432 vs 2 ± 474 U/L; P < .001). However, reductions in serum levels of K18 were not better than reductions in levels of alanine aminotransferase in identifying adults with histologic improvement (area under the receiver operator characteristic [AUROC], 0.71; 95% confidence interval [CI], 0.63-0.80; vs AUROC, 0.68; 95% CI, 0.61-0.79; P = .34) or children (AUROC, 0.72; 95% CI, 0.63-0.81; vs AUROC, 0.79; 95% CI, 0.70-0.87; P = .42). CONCLUSIONS: Decreases in serum levels of K18 are associated strongly with improved liver histologies in adults or children with NAFLD. However, reductions in K18 do not perform better than those in alanine aminotransferase level in identifying histologic changes in NAFLD.
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    Serum high mobility group box 1 protein levels are not associated with either histological severity or treatment response in children and adults with nonalcoholic fatty liver disease
    (PLOS, 2017-11-02) Yates, Katherine P.; Deppe, Ross; Comerford, Megan; Masuoka, Howard; Cummings, Oscar W.; Tonascia, James; Chalasani, Naga; Vuppalanchi, Raj; Medicine, School of Medicine
    Aim Serum high mobility group box 1 protein (HMGB1) is a proinflammatory molecule that could potentially serve as a biomarker for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) due to its correlation with degree of liver fibrosis. The aim of the current study was to examine the cross-sectional and longitudinal relationships between serum HMGB1 levels and liver histology in adults and children with NAFLD participating in two large randomized controlled trials. Methods Serum HMGB1 levels were measured at various time points in adults and children with NAFLD, who participated in PIVENS and TONIC clinical trials respectively. PIVENS trial compared vitamin E or pioglitazone to placebo in adults whereas TONIC trial compared vitamin E or metformin to placebo in children. Participants had liver biopsies at baseline and the end of treatment (96 weeks), and liver histology was reviewed by a central committee of study pathologists. Results In the cross-sectional analyses (n = 205 for PIVENS and 109 for TONIC), there was no significant relationship between serum HMGB1 levels and histological features such as steatosis, ballooning, inflammation, fibrosis, or presence of steatohepatitis in either adults or children. Serum HMGB1 levels did not change significantly during treatment either with placebo, vitamin E therapy (P = 0.81) or pioglitazone (P = 0.09) in the PIVENS trial. Similarly, serum HMGB1 levels did not change significantly during treatment either with placebo, metformin (P = 0.15) or vitamin E (P = 0.23) in the TONIC trial. In the longitudinal analyses (n = 105 for PIVENS and 109 for TONIC), changes in serum HMGB1 levels did not correlate with histologic improvement or resolution of NASH in either adults or children. There was no relationship between serum HMGB1 and ALT levels in either adults or children with NAFLD. Conclusion Serum HMGB1 levels were not associated with histological severity or treatment response in either children or adults with NAFLD.