Publications by authors named "Wing-Kin Syn"

114 Publications

The contribution of daytime sleepiness to impaired quality of life in NAFLD in an ethnically diverse population.

Sci Rep 2022 03 24;12(1):5123. Epub 2022 Mar 24.

Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, UK.

Health-related quality of life (HRQoL) is lower in people with NAFLD compared to the general population. Sleep disturbance resulting in daytime sleepiness is common in patients with NAFLD, but the effect of daytime sleepiness on HRQoL in NAFLD is unclear. The prevalence and natural history of NAFLD vary in different ethnic groups, but there has been limited ethnic diversity in HrQoL studies to date. We aimed to assess whether daytime sleepiness is independently associated with reduced HRQoL in an ethnically diverse UK population. We conducted HRQoL assessments using SF-36 version 2 and Epworth Sleepiness Scale (ESS) questionnaires in 192 people with NAFLD. Multivariate linear regression was used to identify factors independently affecting HRQoL scales. People with NAFLD reported significantly reduced physical health-related SF-36 scores compared to the general UK population. South Asian NAFLD patients reported impairment in physical health, but not mental health, approximately a decade before White NAFLD patients. In multivariate linear regression, daytime sleepiness (ESS score > 10), was the most significant independent predictor of reduced physical health. Age, BMI and liver stiffness score were also significantly associated. HRQoL is impaired earlier in patients of South Asian ethnicity. ESS score > 10, indicative of excessive daytime sleepiness, is an independent predictor of reduced HRQoL in people with NAFLD regardless of ethnicity. Daytime sleepiness should be considered as a contributing factor to reduced HRQoL in clinical practice and when evaluating patient-related outcomes in clinical trials.
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http://dx.doi.org/10.1038/s41598-022-08358-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8948283PMC
March 2022

Methionine adenosyltransferase 1a antisense oligonucleotides activate the liver-brown adipose tissue axis preventing obesity and associated hepatosteatosis.

Nat Commun 2022 03 1;13(1):1096. Epub 2022 Mar 1.

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, Leioa, Spain.

Altered methionine metabolism is associated with weight gain in obesity. The methionine adenosyltransferase (MAT), catalyzing the first reaction of the methionine cycle, plays an important role regulating lipid metabolism. However, its role in obesity, when a plethora of metabolic diseases occurs, is still unknown. By using antisense oligonucleotides (ASO) and genetic depletion of Mat1a, here, we demonstrate that Mat1a deficiency in diet-induce obese or genetically obese mice prevented and reversed obesity and obesity-associated insulin resistance and hepatosteatosis by increasing energy expenditure in a hepatocyte FGF21 dependent fashion. The increased NRF2-mediated FGF21 secretion induced by targeting Mat1a, mobilized plasma lipids towards the BAT to be catabolized, induced thermogenesis and reduced body weight, inhibiting hepatic de novo lipogenesis. The beneficial effects of Mat1a ASO were abolished following FGF21 depletion in hepatocytes. Thus, targeting Mat1a activates the liver-BAT axis by increasing NRF2-mediated FGF21 secretion, which prevents obesity, insulin resistance and hepatosteatosis.
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http://dx.doi.org/10.1038/s41467-022-28749-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8888704PMC
March 2022

A Potential Role for Bile Acid Signaling in Celiac Disease-Associated Fatty Liver.

Metabolites 2022 Jan 30;12(2). Epub 2022 Jan 30.

Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, In der Schornau 23-25, 44892 Bochum, Germany.

Celiac disease (CeD) is a chronic autoimmune disorder characterized by an intolerance to storage proteins of many grains. CeD is frequently associated with liver damage and steatosis. Bile acid (BA) signaling has been identified as an important mediator in gut-liver interaction and the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to analyze BA signaling and liver injury in CeD patients. Therefore, we analyzed data of 20 CeD patients on a gluten-free diet compared to 20 healthy controls (HC). We furthermore analyzed transaminase levels, markers of cell death, BA, and fatty acid metabolism. Hepatic steatosis was determined via transient elastography, by MRI and non-invasive scores. In CeD, we observed an increase of the apoptosis marker M30 and more hepatic steatosis as compared to HC. Fibroblast growth factor 19 (FGF19) was repressed in CeD, while low levels were associated with steatosis, especially in patients with high levels of anti-tissue transglutaminase antibodies (anti-tTG). When comparing anti-tTG-positive CeD patients to individuals without detectable anti-tTG levels, hepatic steatosis was accentuated. CeD patients with significant sonographic steatosis (defined by CAP ≥ 283 db/m) were exclusively anti-tTG-positive. In summary, our results suggest that even in CeD patients in clinical remission under gluten-free diet, alterations in gut-liver axis, especially BA signaling, might contribute to steatotic liver injury and should be further addressed in future studies and clinical practice.
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http://dx.doi.org/10.3390/metabo12020130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879761PMC
January 2022

Non-Invasive Risk Stratification in NAFLD/NASH Patients for Screening EGD.

Clin Exp Gastroenterol 2022 10;15:1-3. Epub 2022 Jan 10.

Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA.

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http://dx.doi.org/10.2147/CEG.S339850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759994PMC
January 2022

STARD1: a new rising StAR in cholesterol-mediated hepatocarcinogenesis.

Hepatobiliary Surg Nutr 2021 Dec;10(6):910-912

Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA.

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http://dx.doi.org/10.21037/hbsn-21-374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8683904PMC
December 2021

A Review of the Epidemiology, Pathophysiology, and Efficacy of Anti-diabetic Drugs Used in the Treatment of Nonalcoholic Fatty Liver Disease.

Dig Dis Sci 2021 11 19;66(11):3676-3688. Epub 2021 Aug 19.

Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, SC, USA.

In recent years, epidemiological studies have consistently demonstrated that the coexistence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) is strongly associated with increased mortality and morbidity related to hepatic- and extrahepatic causes. Indeed, compared with the general population, patients with T2DM are more likely to be diagnosed with more severe forms of NAFLD (i.e., nonalcoholic steatohepatitis (NASH) with liver fibrosis). There is an ongoing debate whether NALFD is a consequence of diabetes or whether NAFLD is simply a component and manifestation of the metabolic syndrome, since liver fat (steatosis) and even more advanced stages of liver fibrosis can occur in the absence of diabetes. Nevertheless, insulin resistance is a key component of the mechanism of NAFLD development; furthermore, therapies that lower blood glucose concentrations also appear to be effective in the treatment of NAFLD. Here, we will discuss the pathophysiological and epidemiological associations between NAFLD and T2DM. We will also review currently available anti-diabetic agents with their regard to their efficacy of NAFLD/NASH treatment.
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http://dx.doi.org/10.1007/s10620-021-07206-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8510897PMC
November 2021

Anti-TNFα treatment in Crohn's disease: Impact on hepatic steatosis, gut-derived hormones and metabolic status.

Liver Int 2021 11 21;41(11):2646-2658. Epub 2021 Jul 21.

Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany.

Background And Aims: An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor-Necrosis-Factor (TNF) activity, yet it is unclear why anti-TNFα agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti-TNF treatment and hepatic steatosis in CD, focusing on the gut-liver axis.

Methods: This cross-sectional study evaluated patients with established CD, with and without anti-TNFα treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis.

Results: Patients on anti-TNFα treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti-TNFα therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti-TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group-specific alterations with low levels in patients without anti-TNFα treatment. Low abundance of Firmicutes was associated with higher triglyceride levels.

Conclusions: Anti-TNFα treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR-signalling (eg FGF19) and microbiota composition in CD.
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http://dx.doi.org/10.1111/liv.15003DOI Listing
November 2021

Phosphorylation and Stabilization of PIN1 by JNK Promote Intrahepatic Cholangiocarcinoma Growth.

Hepatology 2021 11 15;74(5):2561-2579. Epub 2021 Sep 15.

Leeds Institute of Medical Research at St. James', Faculty of Medicine and Health, University of Leeds, St. James' University Hospital, Leeds, United Kingdom.

Background And Aims: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive type of liver cancer in urgent need of treatment options. Aberrant activation of the c-Jun N-terminal kinase (JNK) pathway is a key feature in ICC and an attractive candidate target for its treatment. However, the mechanisms by which constitutive JNK activation promotes ICC growth, and therefore the key downstream effectors of this pathway, remain unknown for their applicability as therapeutic targets. Our aim was to obtain a better mechanistic understanding of the role of JNK signaling in ICC that could open up therapeutic opportunities.

Approach And Results: Using loss-of-function and gain-of-function studies in vitro and in vivo, we show that activation of the JNK pathway promotes ICC cell proliferation by affecting the protein stability of peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), a key driver of tumorigenesis. PIN1 is highly expressed in ICC primary tumors, and its expression positively correlates with active JNK. Mechanistically, the JNK kinases directly bind to and phosphorylate PIN1 at Ser115, and this phosphorylation prevents PIN1 mono-ubiquitination at Lys117 and its proteasomal degradation. Moreover, pharmacological inhibition of PIN1 through all-trans retinoic acid, a Food and Drug Administration-approved drug, impairs the growth of both cultured and xenografted ICC cells.

Conclusions: Our findings implicate the JNK-PIN1 regulatory axis as a functionally important determinant for ICC growth, and provide a rationale for therapeutic targeting of JNK activation through PIN1 inhibition.
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http://dx.doi.org/10.1002/hep.31983DOI Listing
November 2021

Diagnostic Accuracy of Non-Imaging and Ultrasound-Based Assessment of Hepatic Steatosis Using Controlled Attenuation Parameter (CAP) as Reference.

J Clin Med 2021 Apr 4;10(7). Epub 2021 Apr 4.

Translational Medicine Group, Pomeranian Medical University, 70-204 Szczecin, Poland.

Background & Aims: In view of the limited reliability of biopsies in the assessment of liver fat, a non-invasive, trustworthy, and more accessible method estimating a degree of steatosis is urgently needed. While the controlled attenuation parameter (CAP) is used to quantify hepatic fat, its availability in routine practice is limited. Therefore, the aim of this study was to compare the diagnostic accuracy of biomarker- and ultrasound-based techniques for the diagnosis and grading of hepatic steatosis.

Methods: This was a prospective study of 167 adults with and without non-alcoholic fatty liver disease. As measured against CAP, we assessed Hamaguchi's score and the hepatorenal index (HRI), and the following biochemical measures: the fatty liver index, hepatic steatosis index, and lipid accumulation product scores during a single out-patient visit. Area under the receiver operating curve (AUROC) analyses were used to evaluate the diagnostic accuracy of each test and to calculate optimal thresholds for the ultrasound techniques.

Results: All non-invasive methods displayed high accuracy in detecting steatosis (mean AUC value ≥ 0.90), with Hamaguchi's score and the HRI being the most precise. These two tests also had the highest sensitivity and specificity (82.2% and 100%; 86.9% and 94.8%, respectively). We propose new thresholds for Hamaguchi's score and HRI for hepatic steatosis grading, indicated by optimal sensitivity and specificity.

Conclusions: Ultrasound-based techniques are the most accurate for assessing liver steatosis compared to other non-invasive tests. Given the accessibility of ultrasonography, this finding is of practical importance for the assessment of liver steatosis in clinical settings.
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http://dx.doi.org/10.3390/jcm10071507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038574PMC
April 2021

Targeting myosin 1c inhibits murine hepatic fibrogenesis.

Am J Physiol Gastrointest Liver Physiol 2021 06 28;320(6):G1044-G1053. Epub 2021 Apr 28.

Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina.

Myosin 1c (Myo1c) is an unconventional myosin that modulates signaling pathways involved in tissue injury and repair. In this study, we observed that Myo1c expression is significantly upregulated in human chronic liver disease such as nonalcoholic steatohepatitis (NASH) and in animal models of liver fibrosis. High throughput data from the GEO-database identified similar Myo1c upregulation in mice and human liver fibrosis. Notably, transforming growth factor-β1 (TGF-β1) stimulation to hepatic stellate cells (HSCs), the liver pericyte and key cell type responsible for the deposition of extracellular matrix, upregulates Myo1c expression, whereas genetic depletion or pharmacological inhibition of Myo1c blunted TGF-β-induced fibrogenic responses, resulting in repression of α-smooth muscle actin (α-SMA) and collagen type I α 1 chain (Col1α1) mRNA. Myo1c deletion also decreased fibrogenic processes such as cell proliferation, wound healing response, and contractility when compared with vehicle-treated HSCs. Importantly, phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) and mothers against decapentaplegic homolog 3 (SMAD3) were significantly blunted upon Myo1c inhibition in GRX cells as well as Myo1c knockout (Myo1c-KO) mouse embryonic fibroblasts (MEFs) upon TGF-β stimulation. Using the genetic Myo1c-KO mice, we confirmed that Myo1c is critical for fibrogenesis, as Myo1c-KO mice were resistant to carbon tetrachloride (CCl4)-induced liver fibrosis. Histological and immunostaining analysis of liver sections showed that deposition of collagen fibers and α-SMA expression were significantly reduced in Myo1c-KO mice upon liver injury. Collectively, these results demonstrate that Myo1c mediates hepatic fibrogenesis by modulating TGF-β signaling and suggest that inhibiting this process may have clinical application in treating liver fibrosis. The incidences of liver fibrosis are growing at a rapid pace and have become one of the leading causes of end-stage liver disease. Although TGF-β1 is known to play a prominent role in transforming cells to produce excessive extracellular matrix that lead to hepatic fibrosis, the therapies targeting TGF-β1 have achieved very limited clinical impact. This study highlights motor protein myosin-1c-mediated mechanisms that serve as novel regulators of TGF-β1 signaling and fibrosis.
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http://dx.doi.org/10.1152/ajpgi.00105.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285590PMC
June 2021

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence.

Cells 2020 11 11;9(11). Epub 2020 Nov 11.

Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44892 Bochum, Germany.

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)-the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.
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http://dx.doi.org/10.3390/cells9112458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698018PMC
November 2020

Hepatokines and adipokines in NASH-related hepatocellular carcinoma.

J Hepatol 2021 02 5;74(2):442-457. Epub 2020 Nov 5.

Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto-von-Guericke University Magdeburg, 39120 Magdeburg, Germany; Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany. Electronic address:

The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD-related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, preventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipokines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors - in particular, angiopoietin-like proteins, fibroblast growth factors, and apelin - for detection or even as therapeutic targets in NAFLD-related HCC.
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http://dx.doi.org/10.1016/j.jhep.2020.10.030DOI Listing
February 2021

GPR40 deficiency is associated with hepatic FAT/CD36 upregulation, steatosis, inflammation, and cell injury in C57BL/6 mice.

Am J Physiol Endocrinol Metab 2021 01 26;320(1):E30-E42. Epub 2020 Oct 26.

Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina.

G-protein-coupled receptor 40 (GPR40) is highly expressed in pancreatic islets, and its activation increases glucose-stimulated insulin secretion from pancreas. Therefore, GPR40 is considered as a target for type 2 diabetes mellitus (T2DM). Since nonalcoholic fatty liver disease (NAFLD) is associated with T2DM and GPR40 is also expressed by hepatocytes and macrophages, it is important to understand the role of GPR40 in NAFLD. However, the role of GPR40 in NAFLD in animal models has not been well defined. In this study, we fed wild-type or GPR40 knockout C57BL/6 mice a high-fat diet (HFD) for 20 wk and then assessed the effect of GPR40 deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that an HFD increased body weight, glucose, insulin, insulin resistance, cholesterol, and alanine aminotransferase (ALT), and GPR40 deficiency did not mitigate the HFD-induced metabolic abnormalities. In contrast, we found that GPR40 deficiency was associated with increased body weight, insulin, insulin resistance, cholesterol, and ALT in control mice fed a low-fat diet (LFD). Surprisingly, histology and Oil Red O staining showed that GPR40 deficiency in LFD-fed mice was associated with steatosis. Immunohistochemical analysis showed that GPR40 deficiency also increased F4/80, a macrophage biomarker, in LFD-fed mice. Furthermore, results showed that GPR40 deficiency led to a robust upregulation of hepatic fatty acid translocase (FAT)/CD36 expression. Finally, our in vitro studies showed that GPR40 knockdown by siRNA or a GPR40 antagonist increased palmitic acid-induced FAT/CD36 mRNA in hepatocytes. Taken together, this study indicates that GPR40 plays an important role in homeostasis of hepatic metabolism and inflammation and inhibits nonalcoholic steatohepatitis by possible modulation of FAT/CD36 expression.
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http://dx.doi.org/10.1152/ajpendo.00257.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436599PMC
January 2021

NASH, Metabolic Syndrome, and Diabetes: How Sugar and Fat Increase the Risk of Developing Advanced Liver Disease.

Dig Dis Sci 2021 07 26;66(7):2147-2148. Epub 2020 Sep 26.

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.

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http://dx.doi.org/10.1007/s10620-020-06620-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236040PMC
July 2021

Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease.

Aging Cell 2020 08 7;19(8):e13183. Epub 2020 Jul 7.

Department of Physiology, Faculty of Medicine and Nursing, University of Basque Country UPV/EHU, Leioa, Spain.

Osteopontin (OPN), a senescence-associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age-dependent hepatosteatosis. Thus, we investigated the role of OPN in the age-related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild-type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN-deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN-KO mice liver were associated with the decrease of 78 kDa glucose-regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and CD36 levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in CD36 levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53-OPN axis is required to inhibit the onset of age-related hepatosteatosis.
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http://dx.doi.org/10.1111/acel.13183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431823PMC
August 2020

The Emerging Epidemic of Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: True, True, and Related?

Dig Dis Sci 2020 07;65(7):1885-1887

Division of Cardiology, Department of Internal Medicine, Medical University of South Carolina, 114 Doughty Street, Charleston, SC, 29412, USA.

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http://dx.doi.org/10.1007/s10620-020-06113-9DOI Listing
July 2020

Harnessing liver progenitors in the treatment of liver fibrosis: a step in the right direction?

Gut 2020 06 20;69(6):975-976. Epub 2020 Jan 20.

Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, USA

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http://dx.doi.org/10.1136/gutjnl-2019-320203DOI Listing
June 2020

Proteomic screening of plasma identifies potential noninvasive biomarkers associated with significant/advanced fibrosis in patients with nonalcoholic fatty liver disease.

Biosci Rep 2020 01;40(1)

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, U.S.A.

Noninvasive biomarkers are clinically useful for evaluating liver fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD). The aim of the present study was to compare plasma proteins in patients with early nonalcoholic steatohepatitis (NASH) (F0-F1) versus NASH with significant/advanced fibrosis (F2-F4) to determine whether candidate proteins could be used as potential noninvasive biomarkers. Nineteen biopsy-proven NAFLD patients including ten early NASH patients and nine NASH patients with significant/advanced fibrosis were enrolled in the present study. High-resolution proteomics screening of plasma was performed with the SCIEX TripleTOF 5600 System. Proteins were quantified using two different software platforms, Progenesis Qi and Scaffold Q+, respectively. Progenesis Qi analysis resulted in the discovery of 277 proteins compared with 235 proteins in Scaffold Q+. Five consensus proteins (i.e. Complement component C7; α-2-macroglobulin; Complement component C8 γ chain; Fibulin-1; α-1-antichymotrypsin) were identified. Complement component C7 was three-fold higher in the NASH group with significant/advanced fibrosis (F2-F4) compared with the early NASH (F0-F1) group (q-value = 3.6E-6). Complement component C7 and Fibulin-1 are positively correlated with liver stiffness (P=0.000, P=0.002, respectively); whereas, Complement component C8 γ chain is negatively correlated (P=0.009). High levels of Complement C7 are associated with NASH with significant/advanced fibrosis and Complement C7 is a perfect classifier of patients included in this pilot study. Further studies will be needed in a larger validation cohort to confirm the utility of complement proteins as biomarkers or mechanistic determinants of NASH with significant/advanced fibrosis.
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http://dx.doi.org/10.1042/BSR20190395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944676PMC
January 2020

Amitriptyline inhibits nonalcoholic steatohepatitis and atherosclerosis induced by high-fat diet and LPS through modulation of sphingolipid metabolism.

Am J Physiol Endocrinol Metab 2020 02 10;318(2):E131-E144. Epub 2019 Dec 10.

Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina.

We reported previously that increased acid sphingomyelinase (ASMase)-catalyzed hydrolysis of sphingomyelin, which leads to increases in ceramide and sphingosine 1 phosphate (S1P), played a key role in the synergistic upregulation of proinflammatory cytokines by palmitic acid (PA), a major saturated fatty acid, and lipopolysaccharide (LPS) in macrophages. Since macrophages are vital players in nonalcoholic steatohepatitis (NASH) and atherosclerosis, we assessed the effect of ASMase inhibition on NASH and atherosclerosis cooperatively induced by high-PA-containing high-fat diet (HP-HFD) and LPS in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice were fed HP-HFD, injected with low dose of LPS and treated with or without the ASMase inhibitor amitriptyline. The neutral sphingomyelinase inhibitor GW4869 was used as control. Metabolic study showed that both amitriptyline and GW4869 reduced glucose, lipids, and insulin resistance. Histological analysis and Oil Red O staining showed that amitriptyline robustly reduced hepatic steatosis while GW4869 had modest effects. Interestingly, immunohistochemical study showed that amitriptyline, but not GW4869, strongly reduced hepatic inflammation. Furthermore, results showed that both amitriptyline and GW4869 attenuated atherosclerosis. To elucidate the underlying mechanisms whereby amitriptyline inhibited both NASH and atherosclerosis, but GW4869 only inhibited atherosclerosis, we found that amitriptyline, but not GW4869, downregulated proinflammatory cytokines in macrophages. Finally, we found that inhibition of sphingosine 1 phosphate production is a potential mechanism whereby amitriptyline inhibited proinflammatory cytokines. Collectively, this study showed that amitriptyline inhibited NASH and atherosclerosis through modulation of sphingolipid metabolism in LDLR-/- mice, indicating that sphingolipid metabolism in macrophages plays a crucial role in the linkage of NASH and atherosclerosis.
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http://dx.doi.org/10.1152/ajpendo.00181.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052581PMC
February 2020

Association of rs12979860 polymorphism with HCV-related hepatocellular carcinoma susceptibility in a Chinese population.

Clin Exp Gastroenterol 2019 6;12:433-439. Epub 2019 Nov 6.

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.

Background: The association between interferon lambda-3 (,also known as interleukin 28B, ) rs12979860 polymorphism and the development of hepatocellular carcinoma (HCC) has been investigated in recent studies with inconclusive and inconsistent results. rs12979860 polymorphism has been shown a marked differential distribution with regional and ethnic variation. Whether this single nucleotide polymorphism influences susceptibility to hepatitis C virus (HCV)-related HCC remains elusive.

Methods: In this case-control study, a total of 157 Chinese Han patients with chronic HCV infection were enrolled, including 62 HCV-related HCC patients and 95 chronic hepatitis C (CHC) patients without HCC, and the genetic polymorphism of rs12979860 was genotyped via a DNA microarray-based assay. The logistic regression analysis was employed to determine the correlation between the genetic polymorphism and risk of HCV-related HCC.

Results: A higher proportion of CT/TT genotype and T allele was observed in HCC patients compared to the CHC group. Under the genetic model of allele frequency, the T allele was associated with elevated risk of HCV-related HCC in the Chinese population compared to C allele after an adjustment for age, gender, body mass index, HCV infection duration, and HCV genotypes (=0.046). In the subgroup analysis stratified by HCV genotype, subjects with CHC genotype 1b infection carrying rs12979860 T allele and CT+TT genotype had higher susceptibility to HCC than those with C allele and CC genotype (=0.020, =0.037, respectively).

Conclusion: rs12979860 polymorphism with T allele could be a factor that increases the risk of HCV-related HCC in the Chinese population, especially those subjects with CHC genotype 1b infection.
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http://dx.doi.org/10.2147/CEG.S206194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842746PMC
November 2019

Nonalcoholic Fatty Liver Disease Among Individuals with HIV Mono-infection: A Growing Concern?

Dig Dis Sci 2019 12 23;64(12):3394-3401. Epub 2019 Oct 23.

Section of Gastroenterology and Hepatology, Ralph H. Johnson VAMC, Charleston, SC, USA.

Purpose Of Review: Liver disease is a leading cause of non-AIDS-related death in the HIV population since the introduction of highly active antiretroviral treatment (HAART). Recent studies suggest that patients with HIV are at high risk for nonalcoholic fatty liver disease (NAFLD) and progressive liver fibrosis. Evidence for the prevalence, risk factors, and diagnostic methodologies of NAFLD in patients with HIV mono-infection is summarized here.

Recent Findings: Although limited, published studies suggest that the prevalence of NAFLD is higher (30-50%) and progresses at an increased rate in patients with HIV compared to the general population. Identifying those at risk for significant liver fibrosis is critical, preferably with non-invasive screening tests. While there is a paucity of evidence in this population, transient elastography (TE) appears to provide a sensitive, non-invasive screening modality. Identifying NAFLD early will allow for dietary and lifestyle interventions, as well as future drug therapies to decrease the risk of progressive liver fibrosis and cirrhosis in the high-risk HIV population. Clinicians should be aware of this risk and consider using TE for NAFLD diagnosis and surveillance.
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http://dx.doi.org/10.1007/s10620-019-05861-7DOI Listing
December 2019

Characteristics of amino acid substitutions within the "a" determinant region of hepatitis B virus in chronically infected patients with coexisting HBsAg and anti-HBs.

Clin Res Hepatol Gastroenterol 2020 11 14;44(6):923-931. Epub 2019 Oct 14.

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Section of Gastroenterology, Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, USA; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain. Electronic address:

Objectives: Simultaneous positivity for both hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) is an atypical serological profile in chronic hepatitis B (CHB) patients. The exact mechanisms underlying the uncommon profile remains unclear. The aim of this study was to analyze the characteristics of amino acid substitutions within the "a" determinant region in a large cohort of CHB patients with coexistence of HBsAg and anti-HBs.

Methods: In total 8687 CHB patients, of which 505 had coexisting HBsAg and anti-HBs, were enrolled in this study. Mutations within the "a" determinant region in 131 HBsAg+/anti-HBs+ patients and 150 age and gender matched HBsAg+/anti-HBs- patients were determined by direct sequencing and the characteristics of amino acid substitutions were analyzed.

Results: The prevalence of coexistence of HBsAg and anti-HBs in the CHB patients was 5.81%. Compared to the control subjects, there were more amino acid substitutions in HBsAg+/anti-HBs+ patients (30.5% vs. 12.7%, P<0.001), especially within the first loop of the "a" determinant region. The most frequent amino acid substitution was located at position s126 and the predominant substitution was sI126T in HBsAg+/anti-HBs+ patients with genotype C. The frequency of additional N-glycosylation sites in HBsAg+/anti-HBs+ patients and the control subjects was 3.8% and 0.6%, respectively.

Conclusions: The accumulation and diversity of amino acid variations within "a" determinant region might contribute to the coexistence of HBsAg and anti-HBs. These findings extend understanding of the genetic mechanism of this atypical serological profile in CHB patients.
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http://dx.doi.org/10.1016/j.clinre.2019.08.005DOI Listing
November 2020

Evolving Management Strategies for Nonalcoholic Fatty Liver Disease-Targeting Primary Care Physicians.

Diabetes Technol Ther 2019 11 29;21(11):611-618. Epub 2019 Jul 29.

Division of Endocrinology, Diabetes and Metabolism, University of Virginia, Charlottesville, Virginia.

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http://dx.doi.org/10.1089/dia.2019.0158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360107PMC
November 2019

Low Free Triiodothyronine Is Associated with Advanced Fibrosis in Patients at High Risk for Nonalcoholic Steatohepatitis.

Dig Dis Sci 2019 08 3;64(8):2351-2358. Epub 2019 Jun 3.

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.

Background: Thyroid hormone is critical for tissue-organ development, growth, differentiation, and metabolism. In murine models of advanced nonalcoholic steatohepatitis (NASH), the administration of T3 reduced liver triglyceride, repressed liver inflammation, and attenuated injury. In recent studies of patients with NASH, hypothyroidism was noted to be associated with more advanced NASH. These findings suggest that thyroid hormone function might be a modulator of nonalcoholic fatty liver disease (NAFLD) outcomes.

Aims: Herein, we evaluated the correlation between plasma TSH/free T3 (fT3)/free T4 (fT4) levels and (non-invasive) surrogate markers of NAFLD fibrosis.

Methods: We performed a retrospective analysis of 144 patients who were seen in our NASH outpatient clinic between 2015 and 2017. Each patient underwent a standard anthropometric assessment, laboratory and clinical evaluations, and liver stiffness measurements by transient elastography (Fibroscan). Univariate analysis and multivariate linear and logistic regression analysis were used to identify factors independently associated with NASH and advanced fibrosis.

Results: Low fT3 values but not TSH and fT4 were associated with higher liver stiffness and higher NAFLD fibrosis score, respectively. fT3 and TSH values correlated significantly with indices of liver disease including INR, albumin, ALT, AST, bilirubin, and platelets. In multivariate analyses, a low fT3 was independently associated with high NFS scores (OR 0.169, CI 0.05-0.54, p = 0.003) and was also associated with high liver stiffness readings (OR 0.326, CI 0.135-0.785, p = 0.001).

Conclusion: A low-normal thyroid hormone function is predictive of NASH and advanced fibrosis and may have a pathogenic role in modulating NAFLD outcomes.
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http://dx.doi.org/10.1007/s10620-019-05687-3DOI Listing
August 2019

Fibrosis in Chronic Liver Disease: An Update on Diagnostic and Treatment Modalities.

Drugs 2019 Jun;79(9):903-927

Division of Gastroenterology and Hepatology, Department of Medicine, Medical University of South Carolina, 30 Courtenay Drive, MSC 702, Room 402, Charleston, SC, 29425, USA.

Fibrosis is a common outcome of most chronic inflammatory diseases, characterized by the accumulation of excessive extracellular matrix components. Individuals with progressive liver fibrosis develop cirrhosis, are at risk of developing liver cancer, and may succumb to liver failure. Although a number of specific therapies for different diseases have been developed and successfully used, for example, direct antiviral agents in treatment for hepatitis C, effective and specific antifibrotic therapies are still not available. Liver biopsy remains the gold standard of staging liver fibrosis. However, transient elastography is increasingly being used in clinical trials and in hepatology clinics as part of standard-of-care evaluation because it is easy to use. Magnetic resonance (MR)-elastography is most accurate in evaluating fibrosis stage but is costly and time consuming and thus not readily available. Recent advances, however, have been made in areas of diagnostic and therapeutic modalities, with an increasing number of potential drugs currently in phase II and III trials, particularly in the field of non-alcoholic steatohepatitis-related liver fibrosis. These new drugs target multiple pathways involved in the pathogenesis of chronic liver disease, and we anticipate that some of them may soon be approved for use in patients.
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http://dx.doi.org/10.1007/s40265-019-01126-9DOI Listing
June 2019

Non-nutritive sweeteners and their association with the metabolic syndrome and non-alcoholic fatty liver disease: a review of the literature.

Eur J Nutr 2019 Aug 22;58(5):1785-1800. Epub 2019 May 22.

Division of Gastroenterology and Hepatology, Medical University of South Carolina, 30 Courtenay Drive-STB Suit 249, MSC 702, Charleston, SC, 29425, USA.

Purpose: Non-alcoholic fatty liver disease (NAFLD) is increasing in incidence worldwide, paralleling epidemics in obesity and metabolic syndrome. Widely considered the hepatic manifestation of the metabolic syndrome, NAFLD is associated with significant morbidity, mortality, and increased healthcare costs. There is an abundance of data linking sugar-sweetened beverages, and fructose, in particular, to the metabolic syndrome and NAFLD. As a result, non-nutritive sweeteners (NNSs) are frequently substituted for sugar in drinks and a variety of foods. However, despite the widespread consumption of NNSs, there is growing concern about their impact on metabolic health.

Methods: This review examines the experimental and clinical evidence on non-nutritive sweetener (NNS) consumption and features of the metabolic syndrome, including NAFLD.

Results: Experimental animal studies show that NNS consumption can induce glucose intolerance, increased food consumption, and weight gain, with proposed mechanisms including altered gut microbiome, inhibition of protective intestinal enzymes, and increased appetite. The evidence from clinical studies is more controversial. Observational studies overwhelmingly show an association between NNS consumption and features of the metabolic syndrome, and this includes NAFLD when analyses are not adjusted for obesity. The evidence from randomized-controlled trials in humans is sparse and conflicting, and primarily evaluates weight-related outcomes.

Conclusion: Further research is urgently needed to evaluate NNS consumption and its relationship with NAFLD and the gut microbiome in humans.
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http://dx.doi.org/10.1007/s00394-019-01996-5DOI Listing
August 2019

The motor protein Myo1c regulates transforming growth factor-β-signaling and fibrosis in podocytes.

Kidney Int 2019 07 4;96(1):139-158. Epub 2019 Mar 4.

Department of Medicine, Nephrology Division, Medical University of South Carolina, Charleston, South Carolina, USA. Electronic address:

Transforming growth factor-β (TGF-β) is known to play a critical role in the pathogenesis of many progressive podocyte diseases. However, the molecular mechanisms regulating TGF-β signaling in podocytes remain unclear. Using a podocyte-specific myosin (Myo)1c knockout, we demonstrate whether Myo1c is critical for TGF-β-signaling in podocyte disease pathogenesis. Specifically, podocyte-specific Myo1c knockout mice were resistant to fibrotic injury induced by Adriamycin or nephrotoxic serum. Further, loss of Myo1c also protected from injury in the TGF-β-dependent unilateral ureteral obstruction mouse model of renal interstitial fibrosis. Mechanistic analyses showed that loss of Myo1c significantly blunted TGF-β signaling through downregulation of canonical and non-canonical TGF-β pathways. Interestingly, nuclear rather than the cytoplasmic Myo1c was found to play a central role in controlling TGF-β signaling through transcriptional regulation. Differential expression analysis of nuclear Myo1c-associated gene promoters showed that nuclear Myo1c targeted the TGF-β responsive gene growth differentiation factor (GDF)-15 and directly bound to the GDF-15 promoter. Importantly, GDF15 was found to be involved in podocyte pathogenesis, where GDF15 was upregulated in glomeruli of patients with focal segmental glomerulosclerosis. Thus, Myo1c-mediated regulation of TGF-β-responsive genes is central to the pathogenesis of podocyte injury. Hence, inhibiting this process may have clinical application in treating podocytopathies.
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http://dx.doi.org/10.1016/j.kint.2019.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589397PMC
July 2019

Current treatment options for nonalcoholic fatty liver disease.

Curr Opin Gastroenterol 2019 05;35(3):168-176

Section of Gastroenterology, Ralph H Johnson, VAMC.

Purpose Of Review: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the United States and is strongly associated to the metabolic syndrome. In this review, we will discuss the evidence behind the current recommendations on lifestyle modifications and available treatment options for NAFLD.

Recent Findings: The unrelenting rise in obesity and diabetes epidemic has led to a large healthcare burden from NAFLD and it is projected to continue to grow over the next two decades. Lifestyle modification that leads to weight loss is effective at treating NAFLD, but these modifications require a multidisciplinary approach for success in the real world. Multiple pharmacologic treatment options have been studied with promising results, but none have been approved for treatment in the United States. Clinical trials are on-going to study further pharmacologic treatment alternatives.

Summary: NAFLD is the most common chronic liver disease in United States, and an independent risk factor for mortality. Implementation of lifestyle modifications through a multidisciplinary approach and careful selection of patients for pharmacologic interventions will be essential for successful management of NAFLD.
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http://dx.doi.org/10.1097/MOG.0000000000000528DOI Listing
May 2019

Health and Economic Burden of Nonalcoholic Fatty Liver Disease in the United States and Its Impact on Veterans.

Fed Pract 2019 Jan;36(1):14-19

was a Fellow, and is an Attending Physician at the division of gastroenterology and hepatology at Medical University of South Carolina in Charleston. Wing-Kin Syn also is the Acting Chief in the section of gastroenterology at Ralph H. Johnson Veterans Affairs Medical Center in Charleston. Akshay Shetty is currently a Transplant Hepatology Fellow in the division of digestive diseases at David Geffen School of Medicine, University of California Los Angeles.

NAFLD is a leading cause of chronic liver disease and cirrhosis in the US and is associated with metabolic syndrome, type 2 diabetes, cardiovascular disease, and all-cause mortality.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366581PMC
January 2019

Coming Complications of Nonalcoholic Fatty Liver Disease: Time to GNASH Your Teeth.

Dig Dis Sci 2019 03;64(3):606-608

Section of Gastroenterology, Ralph H Johnson VAMC, Charleston, SC, USA.

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http://dx.doi.org/10.1007/s10620-018-5426-4DOI Listing
March 2019
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