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Item Association of Pancreatic Steatosis With Chronic Pancreatitis, Obesity, and Type 2 Diabetes Mellitus(Lippincott, Williams & Wilkins, 2019-03) Tirkes, Temel; Jeon, Christie Y.; Li, Liang; Joon, Aron Y.; Seltman, Ted A.; Sankar, Meghana; Persohn, Scott A.; Territo, Paul R.; Radiology and Imaging Sciences, School of MedicineObjective: The aim of this study was to determine the association of the pancreatic steatosis with obesity, chronic pancreatitis (CP), and type 2 diabetes mellitus. Methods: Patients (n = 118) were retrospectively identified and categorized into no CP (n = 60), mild (n = 21), moderate (n = 27), and severe CP (n = 10) groups based on clinical history and magnetic resonance cholangiopancreatography using the Cambridge classification as the diagnostic standard. Visceral and subcutaneous compartments were manually segmented, and fat tissue was quantitatively measured on axial magnetic resonance imaging. Results: Pancreatic fat fraction showed a direct correlation with fat within the visceral compartment (r = 0.54). Patients with CP showed higher visceral fat (P = 0.01) and pancreatic fat fraction (P < 0.001): mild, 24%; moderate, 23%; severe CP, 21%; no CP group, 15%. Patients with type 2 diabetes mellitus showed higher pancreatic steatosis (P = 0.03) and higher visceral (P = 0.007) and subcutaneous fat (P = 0.004). Interobserver variability of measuring fat by magnetic resonance imaging was excellent (r ≥ 0.90–0.99). Conclusions: Increased visceral adipose tissue has a moderate direct correlation with pancreatic fat fraction. Chronic pancreatitis is associated with higher pancreatic fat fraction and visceral fat. Type 2 diabetes mellitus is associated with higher pancreatic fat fraction and visceral and subcutaneous adiposity.Item Author Correction: Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction(SpringerNature, 2018-04-16) Rodriguez-Nunez, Ivan; Caluag, Tiffany; Kirby, Kori; Rudick, Charles N.; Dziarski, Roman; Gupta, Dipika; Medicine, School of MedicineA correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.Item Automatic classification of white regions in liver biopsies by supervised machine learning(Elsevier, 2014-04) Vanderbeck, Scott; Bockhorst, Joseph; Komorowski, Richard; Kleiner, David E.; Gawrieh, Samer; Medicine, School of MedicineAutomated assessment of histological features of non-alcoholic fatty liver disease (NAFLD) may reduce human variability and provide continuous rather than semiquantitative measurement of these features. As part of a larger effort, we perform automatic classification of steatosis, the cardinal feature of NAFLD, and other regions that manifest as white in images of hematoxylin and eosin-stained liver biopsy sections. These regions include macrosteatosis, central veins, portal veins, portal arteries, sinusoids and bile ducts. Digital images of hematoxylin and eosin-stained slides of 47 liver biopsies from patients with normal liver histology (n = 20) and NAFLD (n = 27) were obtained at 20× magnification. The images were analyzed using supervised machine learning classifiers created from annotations provided by two expert pathologists. The classification algorithm performs with 89% overall accuracy. It identified macrosteatosis, bile ducts, portal veins and sinusoids with high precision and recall (≥ 82%). Identification of central veins and portal arteries was less robust but still good. The accuracy of the classifier in identifying macrosteatosis is the best reported. The accurate automated identification of macrosteatosis achieved with this algorithm has useful clinical and research-related applications. The accurate detection of liver microscopic anatomical landmarks may facilitate important subsequent tasks, such as localization of other histological lesions according to liver microscopic anatomy.Item Autophagy in non-alcoholic fatty liver disease and alcoholic liver disease(Elsevier, 2018-09) Khambu, Bilon; Yan, Shengmin; Huda, Nazmul; Liu, Gang; Yin, Xiao-Ming; Pathology and Laboratory Medicine, School of MedicineAutophagy is an evolutionarily conserved intracellular degradative function that is important for liver homeostasis. Accumulating evidence suggests that autophagy is deregulated during the progression and development of alcoholic and non-alcoholic liver diseases. Impaired autophagy prevents the clearance of excessive lipid droplets (LDs), damaged mitochondria, and toxic protein aggregates, which can be generated during the progression of various liver diseases, thus contributing to the development of steatosis, injury, steatohepatitis, fibrosis, and tumors. In this review, we look at the status of hepatic autophagy during the pathogenesis of alcoholic and non-alcoholic liver diseases. We also examine the mechanisms of defects in autophagy, and the hepato-protective roles of autophagy in non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), focusing mainly on steatosis and liver injury. Finally, we discuss the therapeutic potential of autophagy modulating agents for the treatment of these two common liver diseases.Item Defining the serum proteomic signature of hepatic steatosis, inflammation, ballooning and fibrosis in non-alcoholic fatty liver disease(Elsevier, 2023) Sanyal, Arun J.; Williams, Stephen A.; Lavine, Joel E.; Neuschwander-Tetri, Brent A.; Alexander, Leigh; Ostroff, Rachel; Biegel, Hannah; Kowdley, Kris V.; Chalasani, Naga; Dasarathy, Srinivasan; Diehl, Anna Mae; Loomba, Rohit; Hameed, Bilal; Behling, Cynthia; Kleiner, David E.; Karpen, Saul J.; Williams, Jessica; Jia, Yi; Yates, Katherine P.; Tonascia, James; Medicine, School of MedicineBackground & aims: Despite recent progress, non-invasive tests for the diagnostic assessment and monitoring of non-alcoholic fatty liver disease (NAFLD) remain an unmet need. Herein, we aimed to identify diagnostic signatures of the key histological features of NAFLD. Methods: Using modified-aptamer proteomics, we assayed 5,220 proteins in each of 2,852 single serum samples from 636 individuals with histologically confirmed NAFLD. We developed and validated dichotomized protein-phenotype models to identify clinically relevant severities of steatosis (grade 0 vs. 1-3), hepatocellular ballooning (0 vs. 1 or 2), lobular inflammation (0-1 vs. 2-3) and fibrosis (stages 0-1 vs. 2-4). Results: The AUCs of the four protein models, based on 37 analytes (18 not previously linked to NAFLD), for the diagnosis of their respective components (at a clinically relevant severity) in training/paired validation sets were: fibrosis (AUC 0.92/0.85); steatosis (AUC 0.95/0.79), inflammation (AUC 0.83/0.72), and ballooning (AUC 0.87/0.83). An additional outcome, at-risk NASH, defined as steatohepatitis with NAFLD activity score ≥4 (with a score of at least 1 for each of its components) and fibrosis stage ≥2, was predicted by multiplying the outputs of each individual component model (AUC 0.93/0.85). We further evaluated their ability to detect change in histology following treatment with placebo, pioglitazone, vitamin E or obeticholic acid. Component model scores significantly improved in the active therapies vs. placebo, and differential effects of vitamin E, pioglitazone, and obeticholic acid were identified. Conclusions: Serum protein scanning identified signatures corresponding to the key components of liver biopsy in NAFLD. The models developed were sufficiently sensitive to characterize the longitudinal change for three different drug interventions. These data support continued validation of these proteomic models to enable a "liquid biopsy"-based assessment of NAFLD.Item Duodenal mucosal resurfacing for nonalcoholic fatty liver disease(Wiley, 2022-11-25) Shamseddeen, Hani; Vuppalanchi, Raj; Gromski, Mark A.; Medicine, School of MedicineContent available: Author Interview and Audio Recording.Item Elucidating the Role of Biliary Senescence and Mast Cell-Mediated Therapy in Non-Alcoholic Fatty Liver Disease(2023-05) Kundu, Debjyoti; Francis, Heather; Dong, Charlie X.; Alpini, Gianfranco; Linnemann, Amelia; Ekser, BurcinNon-alcoholic fatty liver disease, or NAFLD, is characterized by excess fat deposition in the liver. Cellular senescence is a critical hallmark of NAFLD. Cholangiocytes in the liver plays a significant role in the progression of fatty liver by contributing to senescence. p16 is the main senescent protein expressed by cholangiocytes in primary sclerosing cholangitis (PSC). Thus, we aimed to downregulate p16 by vivo-morpholino and evaluate the disease phenotypes and signaling mechanisms in a murine model of NAFLD. We found that downregulation of p16 reduced i) steatosis), ii) inflammation, iii) fibrosis, and cholangiocyte proliferation in HFD mice compared to the HFD-fed, control vivo-morpholino injected mice. Moreover, the downregulation of p16 reduced insulin-like growth factor-1 (IGF-1) in cholangiocytes, previously identified by our laboratory as a principal SASP factor secreted from cholangiocytes during NAFLD. By ingenuity pathway analysis, we found that p16 might regulates IGF-1 expression via the E2F1/FOXO1axis. Further analyses indicate that p16 downregulation reduces E2F1 mRNA transcription, inhibiting FOXO1 and subsequent IGF-1 expression in cholangiocytes. The presence of mast cells in the liver has been implicated in multiple cholangiopathies. Our lab demonstrated that mast cell stabilization by cromolyn sodium treatment reduced histamine secretion, fibrosis, and biliary proliferation in Mdr2-/- mice, a model of PSC. Thus, we aimed to determine mast cell stabilization as a therapeutic approach to managing NAFLD and its more advanced form, NASH. We found that cromolyn sodium ameliorated i) serum histamine levels, ii) intrahepatic mast cells, iii) inflammation, iv) fibrosis, v) steatosis, and cholangiocyte proliferation in methionine choline deficient diet-fed mice compared to the saline controls. Overall, we report that amelioration of senescence is a critical factor in improving the disease phenotypes in NAFLD. Biliary senescence plays a crucial role in modulating the disease progression in NAFLD, and mast cell stabilization can be used as a therapeutic approach to reduce pathological hallmarks of fatty liver.Item Epidermal growth factor receptor restoration rescues the fatty liver regeneration in mice(American Physiological Society, 2017-10-01) Zimmers, Teresa A.; Jin, Xiaoling; Zhang, Zongxiu; Jiang, Yanlin; Koniaris, Leonidas G.; Surgery, School of MedicineHepatic steatosis is a common histological finding in obese patients. Even mild steatosis is associated with delayed hepatic regeneration and poor outcomes following liver resection or transplantation. We sought to identify and target molecular pathways that mediate this dysfunction. Lean mice and mice made obese through feeding of a high-fat, hypercaloric diet underwent 70 or 80% hepatectomy. After 70% resection, obese mice demonstrated 100% survival but experienced increased liver injury, reduced energy stores, reduced mitoses, increased necroapoptosis, and delayed recovery of liver mass. Increasing liver resection to 80% was associated with mortality of 40% in lean and 80% in obese mice (P < 0.05). Gene expression profiling showed decreased epidermal growth factor receptor (EGFR) in fatty liver. Meta-analysis of expression studies in mice, rats, and patients also demonstrated reduction of EGFR in fatty liver. In mice, both EGFR and phosphorylated EGFR decreased with increasing percent body fat. Hydrodynamic transfection of EGFR plasmids in mice corrected fatty liver regeneration, reducing liver injury, increasing proliferation, and improving survival after 80% resection. Loss of EGFR expression is rate limiting for liver regeneration in obesity. Therapies directed at increasing EGFR in steatosis might promote liver regeneration and survival following hepatic resection or transplantation.Item The eukaryotic initiation factor 2 kinase GCN2 protects against hepatotoxicity during asparaginase treatment(American Physiological Society, 2013-11) Wilson, Gabriel J.; Bunpo, Piyawan; Cundiff, Judy K.; Wek, Ronald C.; Anthony, Tracy G.; Biochemistry & Molecular Biology, School of MedicineAsparaginase is an important drug in the treatment regimen for acute lymphoblastic leukemia. Asparaginase depletes circulating asparagine and glutamine, activating an amino acid stress response (AAR) involving phosphorylation of eukaryotic initiation factor 2 (eIF2) by general control nonderepressible kinase 2 (GCN2). We hypothesized that GCN2 functions to mitigate hepatic stress during asparaginase therapy by activating the AAR. To test this idea, C57BL/6J wild-type mice (Gcn2(+/+)) and those deleted for Gcn2 (Gcn2(-/-)) were injected with asparaginase or saline excipient one time daily for 1 or 6 days. In liver, increased phosphorylation of eIF2 and mRNA expression of AAR target genes activating transcription factor 4, asparagine synthetase, eIF4E-binding protein 1, and CAAT enhancer-binding protein homologous protein were significantly blunted or blocked in the liver of Gcn2(-/-) mice. Loss of AAR during asparaginase coincided with increases in mammalian target of rapamycin signaling, hepatic triglyceride accumulation, and DNA damage in association with genetic markers of oxidative stress (glutathione peroxidase) and inflammation (tumor necrosis factor alpha-α). Although asparaginase depleted circulating asparagine in both Gcn2(+/+) and Gcn2(-/-) mice, all other amino acids, including plasma glutamine, were elevated in the plasma of Gcn2(-/-) mice. This study shows that loss of GCN2 promotes oxidative stress and inflammatory-mediated DNA damage during asparaginase therapy, suggesting that patients with reduced or dysfunctional AAR may be at risk of developing hepatic complications during asparaginase treatment.Item FOXO transcription factors in non-alcoholic fatty liver disease(Elsevier, 2017-09) Dong, X. Charlie; Biochemistry and Molecular Biology, School of MedicineNon-alcoholic fatty liver disease (NAFLD) is a chronic progressive liver disorder that begins with simple hepatic steatosis and progresses to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and even liver cancer. As the global prevalence of NAFLD rises, it is increasingly important that we understand its pathogenesis and develop effective therapies for this chronic disease. Forkhead box O (FOXO) transcription factors are key downstream regulators in the insulin/insulin-like growth factor 1 (IGF1) signaling pathway, and have been implicated in a range of cellular functions including the regulation of glucose, triglyceride, and cholesterol homeostasis. The role of FOXOs in the modulation of immune response and inflammation is complex, with reports of both pro- and anti-inflammatory effects. FOXOs are reported to protect against hepatic fibrosis by inhibiting proliferation and transdifferentiation of hepatic stellate cells. Mice that are deficient in hepatic FOXOs are more susceptible to non-alcoholic steatohepatitis than wild-type controls. In summary, FOXOs play a critical role in maintaining metabolic and cellular homeostasis in the liver, and dysregulation of FOXOs may be involved in NAFLD development.