3 results on '"Mirshahi, Faridoddin"'
Search Results
2. Identification of a metabolic, transcriptomic and molecular signature of PNPLA3-mediated acceleration of steatohepatitis
- Author
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Banini, Bubu A, Kumar, Divya. P., Cazanave, Sophie, Seneshaw, Mulugeta, Mirshahi, Faridoddin, Santhekadur, Prasanna K., Wang, Liangsu, Guan, Hong Ping, Oseini, Abdul, Alonso, Cristina, Bedossa, Pierre, Koduru, Srinivas V., Min, Hae-Ki, and Sanyal, Arun J.
- Subjects
Liver Cirrhosis ,Male ,Polymorphism, Genetic ,Gene Expression ,Membrane Proteins ,Hep G2 Cells ,Lipase ,Diet, High-Fat ,Article ,Mice, Inbred C57BL ,Disease Models, Animal ,Mice ,Diet, Western ,Non-alcoholic Fatty Liver Disease ,Mutation ,Disease Progression ,Hepatic Stellate Cells ,Hepatocytes ,Animals ,Humans ,Transcriptome - Abstract
BACKGROUND & AIMS: The mechanisms by which the I148M mutant variant of the patatin-like phospholipase domain-containing 3 (PNPLA3(I148M)) drives development of nonalcoholic steatohepatitis (NASH) is not known. The aim of this study was to obtain insights on mechanisms underlying PNPLA3(I148M) induced acceleration of NASH. APPROACH & RESULTS: Hepatocyte-specific overexpression of empty vector (Luc), human wild-type PNPLA3 (PNPLA3(WT)), or PNPLA3(I148M) was achieved using adeno-associated virus (AAV)-8 in DIAMOND mice followed by chow diet or high fat Western diet with ad lib administration of sugar in drinking water (WDSW) for 8 weeks. Under WDSW, PNPLA3(I148M) overexpression accelerated steatohepatitis with increased steatosis, inflammation ballooning and fibrosis (p< 0.001 vs other groups for all). Silencing PNPLA3(I148M) after its initial overexpression abrogated these findings. PNPLA3(I148M) caused 22:6n3 docosahexanoic acid depletion and increased ceramides under WDSW in addition to increasing triglycerides and diglycerides especially enriched with unsaturated fatty acids. It also increased oxidative stress and ER-stress. Increased total ceramides was associated with STAT3 activation with downstream activation of multiple immune-inflammatory pathways at a transcriptomic level by network analyses. Silencing PNPLA3(I148M) reversed STAT3 activation. Conditioned media from HepG2 cells overexpressing PNPLA3(I148M) increased procollagen mRNA expression in LX2 cells; this was abrogated by hepatocyte STAT3 inhibition. CONCLUSIONS: Under WDSW, PNPLA3(I148M) overexpression promotes steatosis and NASH by metabolic reprogramming characterized by increased triglycerides and diglycerides, n3 PUFA depletion and increased ceramides with resultant STAT3 phosphorylation and downstream inflammatory pathway activation driving increased stellate cell fibrogenic activity.
- Published
- 2020
3. Haptoglobin 2 Allele is Associated With Histologic Response to Vitamin E in Subjects With Nonalcoholic Steatohepatitis
- Author
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Banini, Bubu A, Cazanave, Sophie C, Yates, Katherine P, Asgharpour, Amon, Vincent, Robert, Mirshahi, Faridoddin, Le, Peter, Contos, Melissa J, Tonascia, James, Chalasani, Naga P, Kowdley, Kris V, McCullough, Arthur J, Behling, Cynthia A, Schwimmer, Jeffrey B, Lavine, Joel E, Sanyal, Arun J, and Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)
- Subjects
Adult ,Male ,nonalcoholic fatty liver disease ,Genotype ,Clinical Trials and Supportive Activities ,Chronic Liver Disease and Cirrhosis ,Clinical Sciences ,vitamin E ,haptoglobin genotype ,Oral and gastrointestinal ,Hepatitis ,Non-alcoholic Fatty Liver Disease ,Clinical Research ,Complementary and Integrative Health ,Humans ,oxidative stress ,nonalcoholic steatohepatitis ,Alleles ,Randomized Controlled Trials as Topic ,Haptoglobins ,Gastroenterology & Hepatology ,Liver Disease ,Treatment Outcome ,Nonalcoholic Steatohepatitis Clinical Research Network ,Female ,Digestive Diseases - Abstract
BackgroundHaptoglobin (Hp) genotype has been linked to oxidative stress and cardiovascular outcomes in response to vitamin E (VitE) among patients with diabetes mellitus. Its effect on histologic response to VitE in nonalcoholic steatohepatitis (NASH) is unknown.GoalsOur objective was to determine if Hp genotype associates with response to VitE in patients with NASH.StudyA post hoc analysis of 228 patients receiving VitE or placebo in 2 clinical trials was performed. Regression analysis was used to assess the effect of VitE versus placebo, by Hp genotype (1-1, 2-1, or 2-2), on histologic features and laboratory markers of nonalcoholic fatty liver disease, comparing baseline to end of treatment values. An interaction term was included in the regression models to assess differential treatment effect across Hp genotype.ResultsHp 2-2 patients treated with VitE versus placebo showed significant histologic improvement (51% vs. 20%; OR=4.2; P=0.006), resolution of steatohepatitis (44% vs. 12%; OR=6.2; P=0.009), decrease in nonalcoholic fatty liver disease Activity Score (NAS) (-2.2 vs. -0.6; P=0.001), and decrease in liver enzymes alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase. Hp 2-1 patients on VitE versus placebo showed improved resolution of steatohepatitis, NAS and liver enzymes. Hp 1-1 patients showed no significant improvement in histology or liver enzymes. VitE had no effect on fibrosis stage in any group. Regression analysis showed incremental benefit of having Hp 2-2 or 2-1 versus 1-1 for all liver enzyme.ConclusionsHp 2 allele is associated with greater histologic and biological improvement in NASH with VitE treatment compared with the Hp 1 allele.
- Published
- 2019
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