Obesity-associated Liver Research Articles

Anti-obesity effects and underlying molecular mechanisms of the ethanolic extract of figs from Ficus hispida using high fat-fed wister rats

Obesity is a known risk factor for many chronic diseases and a substantial threat to public health. We investigated the effects of figs sourced from Ficus hispida on a high fat-fed experimental rat model. We found that a 500-mg dose of ethanolic extract of figs (EFH) reduced oxidative stress markers nitric oxide (NO), malondialdehyde (MDA), and advanced oxidation protein products (AOPP), which were increased in high fat-fed rats. Antioxidant enzymes superoxide dismutase (SOD), catalase, reduced glutathione (GSH), and myeloperoxidase (MPO), found elevated in high fat-fed rats, were also normalized to nearly regular levels by fig treatment. Administration of EFH further reduced fat deposition and expression of adipogenic genes leptin, fatty acid synthase (FAS), peroxisome proliferator-activated receptor gamma (PPARγ), and sterol regulatory element-binding protein-1c (SERBP-1c). Our results suggest that figs have significant effects on reducing oxidative stress and mitigating obesity-associated liver and adipose tissue abnormalities via suppressing adipogenesis. Thus, we propose that F. hispida has potential benefits in reducing obesity.

Sodium-glucose cotransporter-2 inhibitor (SGLT2i) plus glucagon-like peptide type 1 receptor combination is more effective than SGLT2i plus dipeptidyl peptidase-4 inhibitor combination in treating obese mice metabolic dysfunction-associated steatotic liver disease (MASLD).

Monotherapy to treat obesity-associated liver insult is limited. In diet-induced obese mice showing metabolic dysfunction-associated steatotic liver disease (MASLD), we aimed to compare the combinations of sodium-glucose cotransporter-2 inhibitor (SGLT2i, empagliflozin, E), dipeptidyl peptidase-4 inhibitor (DPP4i, linagliptin, L), and glucagon-like peptide type 1 receptor agonist (GLP1RA, dulaglutide, D). Male 3-month-old C57BL/6J mice were fed for 12 weeks in a control (C, n= 10) or high-fat (HF, n= 30) diet. Then, mice were followed for three additional weeks: C, HF, HF E + L, and HF E + D (n= 10/group). HF versus C showed higher hepatic triacylglycerol (TAG, +82%), steatosis (+850%), glucose intolerance (+71%), insulin (+98%), and insulin resistance (+68%). Compared to the HF group, HF E + L showed lower glucose intolerance (-60%), insulin (-61%), insulin resistance (-46%), TAG (-61%), and steatosis (-58%), and HF E + D showed lower glucose intolerance (-71%), insulin (-58%), insulin resistance (-62%), TAG (-61%), and steatosis (-82%). The principal component analysis (PCA) placed the HF group and the HF E + D group on opposite sides, while the HF E + L group was placed between C and HF E + D. PCA separated the groups considering the metabolism-related genes (glucose and lipid), mitochondrial biogenesis, and steatosis. The two pharmacological combinations showed beneficial effects in treating obesity and MASLD. However, the combination of SGLT2i and GLP1RA showed more potent beneficial effects on MASLD than SGLT2i and DPP4i and, therefore, should be the recommended combination.

Hepatokines as Biomarkers of Obesity-Associated Liver Pathophysiology: Deciphering Advances in Basic and Clinical Aspects

Hepatokines are specialized secretory proteins of the liver that play pivotal role in regulation of metabolic homeostasis as well as ensure crosstalk of liver to other organs. In recent years, the correlation of hepatokines and hepatic diseases has been exhibited, positively. Several stimuli, particularly hepatic steatosis provoke dysregulation in metabolic homeostasis and subsequently, pathogenesis of liver diseases that influence expression and release of hepatokines. In this review, we have interlinked the association of hepatic steatosis, a hallmark of obesity, to liver and liver-derived hepatokines. Furthermore, we summarized briefly the impact of several etiologically and epidemiologically important hepatokines, including Fetuin-A, fibroblast growth factor-21 (FGF-21), selenoprotein P, sexual hormone binding globulin (SHBG), angiopoietin like 4 (ANGPTL4) and leukocyte cell-derived chemotaxin (LECT2), in health and disease. Such hepatokines could serve as non-invasive biomarkers of early stages of liver pathogenesis and might contribute in improving patient safety profile for screening purposes and expediting drug development.

Osteopontin-driven T-cell accumulation and function in adipose tissue and liver promoted insulin resistance and MAFLD.

This study investigated the contribution of osteopontin/secreted phosphoprotein 1 (SPP1) to T-cell regulation in initiation of obesity-driven adipose tissue (AT) inflammation and macrophage infiltration and the subsequent impact on insulin resistance (IR) and metabolic-associated fatty liver disease (MAFLD) development. SPP1 and T-cell marker expression was evaluated in AT and liver according to type 2 diabetes and MAFLD in human individualswith obesity. The role of SPP1 on T cells was evaluated in Spp1-knockout mice challenged with a high-fat diet. In humanswith obesity, elevated SPP1 expression in AT was parallel to T-cell marker expression (CD4, CD8A) and IR. Weight loss reversed AT inflammation with decreased SPP1 and CD8A expression. In liver, elevated SPP1 expression correlated with MAFLD severity and hepatic T-cell markers. In mice, although Spp1 deficiency did not impact obesity, it did improve AT IR associated with prevention of proinflammatory T-cell accumulation at the expense of regulatory T cells. Spp1 deficiency also decreased ex vivo helper T cell, subtype 1 (Th1)polarization of AT CD4+ and CD8+ T cells. In addition, Spp1 deficiency significantly reduced obesity-associated liver steatosis and inflammation. Current findings highlight a critical role of SPP1 in the initiation of obesity-driven chronic inflammation by regulating accumulation and/or polarization of T cells. Early targeting of SPP1 could be beneficial for IR and MAFLD treatment.

P31-045-23 The Differential Effects of Silibinin on Obesity-Associated Visfatin and Liver Cancer

P31-045-23 The Differential Effects of Silibinin on Obesity-Associated Visfatin and Liver Cancer

P31-063-23 Targeting iNAMPT To Break the Obesity-Associated Liver Cancer Link: An In Vitro and In Vivo Approach

P31-063-23 Targeting iNAMPT To Break the Obesity-Associated Liver Cancer Link: An In Vitro and In Vivo Approach

Adipose tissue-derived exosomes contribute to obesity-associated liver diseases in long-term high-fat diet-fed mice, but not in short-term.

Our study aimed to investigate the changes in hepatic endoplasmic reticulum (ER) stress, inflammation, insulin signaling, and lipid metabolism during the administration of a high-fat diet (HFD) in mice in order to identify correlations between obesity and metabolic disease development in the liver. We used short-, medium-, and long-term HFD periods, corresponding to 4, 8, and 12 weeks, respectively, and isolated exosomes from adipose tissue. We confirmed the effect of adipose tissue-derived exosomes on metabolic disorders in obesity in alpha mouse liver 12 (AML12) hepatocytes. Adipose tissue-derived exosomes from HFD mice did not affect the AML12 cells after 4 weeks, but ER stress, inflammatory response, insulin resistance, and lipid synthesis were observed after 8 and 12 weeks. Furthermore, we confirmed that an HFD increases the amount of adipose tissue-derived exosomes in mice. Consequently, we can infer that adipose tissue-derived exosomes from HFD-fed mice significantly increase ER stress, inflammatory response, insulin resistance, and lipid synthesis in AML12 cells. Our results demonstrate that obesity alters the effects of adipose tissue-derived exosomes in the liver, potentially becoming a risk factor in the development of obesity-induced liver diseases.

Inflammasome-Mediated Cytokines: A Key Connection between Obesity-Associated NASH and Liver Cancer Progression.

Liver cancer is one of the most lethal malignancies and is commonly diagnosed as hepatocellular carcinoma (HCC), a tumor type that affects about 90% of patients. Non-alcoholic steatohepatitis (NASH) and obesity are both risk factors for this disease. HCC initiation and progression are deeply linked with changes in the hepatic microenvironment, with cytokines playing key roles. The understanding of the pathogenic pathways that connect these disorders to liver cancer remains poor. However, the inflammasome-mediated cytokines associated with both diseases are central actors in liver cancer progression. The release of the pro-inflammatory cytokines IL-1β and IL-18 during inflammasome activation leads to several detrimental effects on the liver microenvironment. Considering the critical crosstalk between obesity, NASH, and HCC, this review will present the connections of IL-1β and IL-18 from obesity-associated NASH with HCC and will discuss approaches to using these cytokines as therapeutic targets against HCC.

Abstract PO006: The Role of Obesity-associated Allograft Inflammatory Factor-1 in Liver Cancer Cell Growth

Abstract Introduction: Obesity is a risk factor in the development of liver cancer. The obesogenic tumor microenvironment is of particular importance in liver tumorigenesis due in part to lipid accumulation and monocyte recruitment which differentiate into pro-inflammatory macrophages. A novel macrophage-associated protein, whose role in obesity-associated liver tumorigenesis has yet to be explored, is allograft inflammatory-factor 1 (AIF-1). AIF-1 is a calcium binding inflammation response scaffold protein. Although, proliferation and migration have been studied, https://scholar.google.com/citations?view_op=view_citation&hl=en&user=AAeKZnoAAAAJ&sortby=pubdate&citation_for_view=AAeKZnoAAAAJ:8dzOF9BpDQo Cactivation of kinase pathways, cell survival, cell death, ROS production and lipogenesis have yet to be explored. AIF-1 is upregulated in both liver cancer and obese individuals. Our research objective is to determine the functional role of AIF-1 in promoting physiological processes important for liver tumorigenesis including proliferation, survival, ROS, and lipogenesis, and 2) determine the contribution of Akt and Erk in promoting this in-vitro phenotype. Methods: HepG2 and SNU-449 liver cancer cells were exposed to AIF-1 (10uM) with or without 10 μM ly294002 (PI3K inhibitor), 10 μM PD98059 (MAPK inhibitor), or 5μM NPS-2143 (calcium sensing receptor inhibitor). Cells were assessed for proliferation, ROS production, lipogenesis, cytotoxicity, and cell survival. Immunoblot analysis was used to measure phosphorylated Akt, Erk, IL-6, and NF-kB protein levels. Results: AIF-1 increased proliferation in HepG2 and SNU-449 liver cancer cells. Inhibiting Akt, and Erk signaling decreased AIF-1-induced proliferation while NPS-2143 CaSR inhibitor decreased proliferation only in HepG2 cells. AIF-1 promoted ROS production and the addition of Akt inhibitor blocked AIF-1 ROS production in both cell lines. Significant differences in lipogenesis were not observed among various treatments in HepG2 and SNU-449 cells. AIF-1 increased cell survival, cytotoxicity and phosphorylation of Akt and Erk, when compared to control. Conclusions: Obesity-associated AIF-1 increased proliferation, ROS, and survival while differential effects were observed with Akt or Erk inhibition. Citation Format: Jessie Waltenbaugh, Curissa Groll, Kelsie Raign, Ramona Price. The Role of Obesity-associated Allograft Inflammatory Factor-1 in Liver Cancer Cell Growth [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO006.

Abstract PO005: Obesity-associated Visfatin, and Silibinin in an In Vitro and In Vivo Model of Liver Cancer

Abstract Introduction: Obesity, specifically body fatness, is a risk factor for the development of liver cancer. The link between obesity and liver cancer is likely to be mediated in part by a state of chronic inflammation. However, it has yet to be determined if visfatin inhibition, a pro-inflammatory adipocytokine upregulated by obesity, is sufficient to prevent or delay the progression of liver cancer. Obesity-induced inflammatory factors may promote cancer progression by increasing cell proliferation, motility, invasion, and metastasis.The use of dietary compounds may break the pro-inflammatory cycle induced by the obese state, thus attenuating the cancer process. Silibinin, a polyphenol in milk thistle seed, has been shown to have anti-inflammatory properties. Studies have yet to determine whether silibinin can be used to break the obesity-cancer link to delay progression of liver cancer. The objective of this cell culture and mouse study is to determine the efficacy of silibinin in the prevention of obesity-associated liver cancer progression. Methods: SNU-449 and HepG2 liver cancer cells were exposed to the following experimental conditions; control, FBS, visfatin (80 ng/ml), visfatin + silibinin 40 μM, silibinin (40 μM). Cell proliferation, lipogenesis, lactate dehydrogenase secretion, and ROS production were measured. Immunoblot was used to measure phospho-Akt, phospho-Erk, NF-kB, Bcl-xL, and actin. Eight-week-old C57BL/6J male mice were randomized to a high-fat DIO (n=6) or control diet (n=6). At 14 weeks, mice will be injected subcutaneously with syngeneic Hepa1-6 murine liver cancer cells. At 15-weeks, mice will receive peritoneal injections of silibinin 3 times per week for 2 weeks. Tumors will be measured and assessed for visfatin, Akt, Erk, and NF-kB protein expression. Results from the animal study are on-going and will be presented at time of the conference. Results: SNU-449 and HepG2 cells exposed to visfatin significantly increased cell proliferation and lipogenesis when compared to control. Further, the addition of silibinin inhibited the visfatin-induced proliferation and lipogenesis in both cell lines. Visfatin increased the phosphorylation of Akt and Erk, and NF-kB expression in both liver cancer cell lines. The addition of silibinin differently suppressed phosphorylation of Akt and Erk in SNU-449 and HepG2 cells. Conclusion: Silibinin differentially inhibits visfatin-induced cell growth, lipogenesis, and promotes cytotoxicity which may lead to increased cancer cell death. Citation Format: Elisa Pedone, Kelly N Green, Kelly R Thornton, Ramona S. Price. Obesity-associated Visfatin, and Silibinin in an In Vitro and In Vivo Model of Liver Cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO005.

The future health and economic burden of obesity-attributable type 2 diabetes and liver disease among the working-age population in Saudi Arabia.

BackgroundObesity and type 2 diabetes (T2DM) are increasing in Saudi Arabia (SA). Among other conditions, these risk factors increase the likelihood of non-alcoholic fatty liver disease (NAFLD), which in turn increases risks for advanced liver diseases, such as non-alcoholic steatohepatitis (NASH), cirrhosis and cancer. The goal of this study was to quantify the health and economic burden of obesity-attributable T2DM and liver disease in SA.MethodsWe developed a microsimulation of the SA population to quantify the future incidence and direct health care costs of obesity-attributable T2DM and liver disease, including liver cancer. Model inputs included population demographics, body mass index, incidence, mortality and direct health care costs of T2DM and liver disease and relative risks of each condition as a function of BMI category. Model outputs included age- and sex-disaggregated incidence of obesity-attributable T2DM and liver disease and their direct health care costs for SA’s working-age population (20–59 years) between 2020 and 2040.ResultsBetween 2020 and 2040, the available data predicts 1,976,593 [± 1834] new cases of T2DM, 285,346 [±874] new cases of chronic liver diseases, and 2,101 [± 150] new cases of liver cancer attributable to obesity, amongst working-age people. By 2040, the direct health care costs of these obesity-attributable diseases are predicted to be 127,956,508,540 [± 51,882,446] USD.ConclusionsThe increase in obesity-associated T2DM and liver disease emphasises the urgent need for obesity interventions and strategies to meaningfully reduce the future health and economic burden of T2DM, chronic liver diseases and liver cancer in SA.

Diet-Induced Obesity Disrupts Histamine-Dependent Oleoylethanolamide Signaling in the Mouse Liver

Introduction: Previous work suggests the existence of a paracrine signaling mechanism in which histamine released from visceral mast cells into the portal circulation contributes to fasting-induced ketogenesis by stimulating biosynthesis of the endogenous high-affinity PPAR-α agonist oleoylethanolamide (OEA). Methods: Male C57Bl/6J mice were rendered obese by exposure to a high-fat diet (HFD; 60% fat). We measured histamine, OEA, and other fatty-acid ethanolamides by liquid-chromatography/mass spectrometry, gene transcription by RT-PCR, protein expression by ELISA, neutral lipid accumulation in the liver using Red Oil O and BODIPY staining, and collagen levels using picrosirius red staining. Results: Long-term exposure to HFD suppressed both fasting-induced histamine release into portal blood and histamine-dependent OEA production in the liver. Additionally, subchronic OEA administration reduced lipid accumulation, inflammatory responses, and fibrosis in the liver of HFD-exposed mice. Discussion: The results suggest that disruption of histamine-dependent OEA signaling in the liver might contribute to pathology in obesity-associated liver steatosis.

Anti-CD47 antibody treatment attenuates liver inflammation and fibrosis in experimental non-alcoholic steatohepatitis models.

With the epidemic burden of obesity and metabolic diseases, nonalcoholic fatty liver disease (NAFLD) including steatohepatitis (NASH) has become the most common chronic liver disease in the western world. NASH may progress to cirrhosis and hepatocellular carcinoma. Currently, no treatment is available for NASH. Therefore, finding a therapy for NAFLD/NASH is in urgent need. Previously we have demonstrated that mice lacking CD47 or its ligand thrombospondin1 (TSP1) are protected from obesity-associated NALFD. This suggests that CD47 blockade might be a novel treatment for obesity-associated metabolic disease. Thus, in this study, the therapeutic potential of an anti-CD47 antibody in NAFLD progression was determined. Both diet-induced NASH mouse model and human NASH organoid model were utilized in this study. NASH was induced in mice by feeding with diet enriched with fat, fructose and cholesterol (AMLN diet) for 20weeks and then treated with anti-CD47 antibody or control IgG for 4weeks. Body weight, body composition and liver phenotype were analysed. We found that anti-CD47 antibody treatment did not affect mice body weight, fat mass or liver steatosis. However, liver immune cell infiltration, inflammation and fibrosis were significantly reduced by anti-CD47 antibody treatment. In vitro data further showed that CD47 blockade prevented hepatic stellate cell activation and NASH progression in a human NASH organoid model. Collectively, these data suggest that anti-CD47 antibody might be a new therapeutic option for obesity-associated NASH and liver fibrosis.

MXD3 Promotes Obesity and the Androgen Receptor Signaling Pathway in Gender-Disparity Hepatocarcinogenesis.

Obesity is closely linked to metabolic diseases, particularly non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD), ultimately leading to hepatocellular carcinoma (HCC). However, the molecular mechanisms of NASH-associated HCC (NAHCC) remain elusive. To explore the impact of Max dimerization protein 3 (MXD3), a transcription factor that regulates several cellular functions in disorders associated with metabolic diseases, we conditionally expressed Mxd3 proteins using Tet-on mxd3 transgenic zebrafish (MXs) with doxycycline (MXs + Dox) or without doxycycline (MXs − Dox) treatment. Overexpression of global MXD3 (gMX) or hepatic Mxd3 (hMX) was associated with obesity-related NAFLD pathophysiology in gMX + Dox, and liver fibrosis and HCC in hMX + Dox. Oil Red O (ORO)-stained signals were seen in intravascular blood vessels and liver buds of larval gMX + Dox, indicating that Mxd3 functionally promotes lipogenesis. The gMX + Dox-treated young adults exhibited an increase in body weight and visceral fat accumulation. The hMX + Dox-treated young adults showed normal body characteristics but exhibited liver steatosis and NASH-like phenotypes. Subsequently, steatohepatitis, liver fibrosis, and NAHCC were found in 6-month-old gMX + Dox adults compared with gMX − Dox adults at the same stage. Overexpression of Mxd3 also enhanced AR expression accompanied by the increase of AR-signaling pathways resulting in hepatocarcinogenesis in males. Our results demonstrate that global actions of Mxd3 are central to the initiation of obesity in the gMX zebrafish through their effects on adipogenesis and that MXD3 could serve as a therapeutic target for obesity-associated liver diseases.

A novel peroxisome proliferator-activated receptor gamma ligand improves insulin sensitivity and promotes browning of white adipose tissue in obese mice

ObjectiveNuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) is a promising target for the treatment of type 2 diabetes. The antidiabetic drug thiazolidinediones (TZDs) are potent insulin sensitizers as full agonists of PPARγ, but cause unwanted side effects. Recent discoveries have shown that TZDs improve insulin sensitivity by blocking PPARγ phosphorylation at S273, which decouples the full agonism-associated side effects. PPARγ ligands that act through the blockage of PPARγ phosphorylation but lack the full agonist activity would be expected to improve insulin sensitivity without TZD-associated side effects, however, chemicals that carry such traits and bind to PPARγ with high-affinity are lacking. Moreover, TZDs are known to promote white-to-brown adipocyte conversion and energy expenditure and appear to require their full agonism on PPARγ for this activity. It is unknown whether a partial or non-TZD agonist of PPARγ is capable of promoting browning effect. In this study, we developed a novel non-TZD partial agonist of PPARγ and investigated its function on insulin sensitivity and white-to-brown conversion and energy expenditure in diet-induced obese mice. MethodsA novel indole-based chemical WO95E was designed via medicinal chemistry and tested for PPARγ binding and activity and for the effect on PPARγ phosphorylation. Diet-induced obese mice were administered with WO95E for 4 weeks. Insulin sensitivity, glucose tolerance, body weight, fat tissue weight, adipocyte size, morphology, energy expenditure, and expression levels of genes involved in PPARγ activity, thermogenesis/browning, and TZD-related side effects were evaluated. ResultsWO95E binds to PPARγ with high affinity and acts as a PPARγ partial agonist. WO95E inhibits PPARγ phosphorylation and regulates PPARγ phosphorylation-dependent genes. WO95E ameliorates insulin resistance and glucose tolerance in mice of diet-induced obesity, with minimal TZD use-associated side effects. We found that WO95E promotes white-to-brown adipocyte conversion and energy expenditure and hence protects against diet-induced obesity. WO95E decreases the size of adipocytes and suppresses adipose tissue inflammation. WO95E also suppresses obesity-associated liver steatosis. ConclusionsWO95E improves insulin sensitivity and glucose homeostasis and promotes browning and energy expenditure by acting as a novel PPARγ phosphorylation inhibitor/partial agonist. Our findings suggest the potential of this compound or its derivative for the therapeutic treatment of insulin resistance and obesity.

Coffee Pulp, a By-Product of Coffee Production, Modulates Gut Microbiota and Improves Metabolic Syndrome in High-Carbohydrate, High-Fat Diet-Fed Rats.

Waste from food production can be re-purposed as raw material for usable products to decrease industrial waste. Coffee pulp is 29% of the dry weight of coffee cherries and contains caffeine, chlorogenic acid, trigonelline, diterpenes and fibre. We investigated the attenuation of signs of metabolic syndrome induced by high-carbohydrate, high-fat diet in rats by dietary supplementation with 5% freeze-dried coffee pulp for the final 8 weeks of a 16-week protocol. Coffee pulp decreased body weight, feed efficiency and abdominal fat; normalised systolic blood pressure, left ventricular diastolic stiffness, and plasma concentrations of triglycerides and non-esterified fatty acids; and improved glucose tolerance in rats fed high-carbohydrate, high-fat diet. Further, the gut microbiota was modulated with high-carbohydrate, high-fat diet and coffee pulp supplementation and 14 physiological parameters were correlated with the changes in bacterial community structures. This study suggested that coffee pulp, as a waste from the coffee industry, is useful as a functional food for improving obesity-associated metabolic, cardiovascular and liver structure and function, and gut microbiota.

Modulatory effect of euxanthone in liver cancer-bearing obese mice: crosstalk between PPARγ and TIMP3 signalling axes.

Liver cancer is one of the prominent cancer-associated fatal diseases with > 80% of cases befall in low-middle resource nations worldwide. In the current study, we studied the effect of euxanthone (EUX) on obesity-associated liver cancer using a high-fat diet-fed mouse model of diethylnitrosamine (DEN)-provoked hepatocellular carcinoma. Mice with 2weeks of age were intraperitoneally injected with diethylnitrosamine (DEN) 25mg/kg b.w. After 4weeks, the mice were divided into four groups with low-fat diet (LFD), high-fat diet (HFD), and EUX treatment groups with or without PPARγ inhibitor (GW9662). We observed that TIMP3, E-cadherin, and Klotho expressions were downmodulated, while MMP9, ADAM17, and Wnt signalling biofactors (Wnt5a, Wnt3a and β-catenin) were upmodulated in the HFD groups. Nevertheless, these aberrations were reciprocated by the treatment with EUX; at the same time, co-administration of PPARγ inhibitor ablated the anti-cancer effects of EUX, indicating that PPARγ activation is a pivotal mechanism underpinning the negative regulation of oncogenic factors by EUX. Together, these results imply that EUX might be a viable therapeutic option in the treatment of obesity-associated hepatocarcinogenesis.

Long-term outcomes of Roux-en-Y gastric bypass or sleeve gastrectomy in patients with cirrhosis; before, during or after liver transplantation: A single center's experience.

The increasing prevalence of morbid obesity (MO) results in parallel growth of obesity-associated liver diseases necessitating liver transplantation (LT). To examine the feasibility and safety of Roux-en-Y gastric bypass or sleeve gastrectomy in the setting of LT. This retrospective chart review included the data on all the MO candidates before and after LT who underwent bariatric surgery (BS) in our institution between 04/2013-09/2016. The reported outcomes were weight change and early and late postoperative complications (mean follow-up: 43±11.1months). Eighteen MO peri-LT patients (10 females, 8 males, average age 48years) were included in the study. Ten had cirrhosis (mean Model of End-stage Liver Disease [MELD] score of 12.5±6.42), three underwent concurrent LT and BS (mean MELD score 23.7±0.58), and five had LT (mean of 56months from LT). The mean percentage of total and excess weight loss was 31% and 81%, respectively. Six of the eight patients with type 2 diabetes mellitus became normoglycemic after BS. Three patients sustained perioperative complications. Two cirrhotic patients died 1 and 4.5years after BS with decompensation. Bariatric surgery appears to effectively address obesity in cirrhotic and LT patients. The surgical risk is higher than that of the regular BS population.

Hepatic Wnt1 Inducible Signaling Pathway Protein 1 (WISP-1/CCN4) Associates with Markers of Liver Fibrosis in Severe Obesity.

Liver fibrosis is a critical complication of obesity-induced fatty liver disease. Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4), a novel adipokine associated with visceral obesity and insulin resistance, also contributes to lung and kidney fibrosis. The aim of the present study was to investigate the role of CCN4 in liver fibrosis in severe obesity. For this, human liver biopsies were collected from 35 severely obese humans (BMI 42.5 ± 0.7 kg/m2, age 46.7 ± 1.8 y, 25.7% males) during bariatric surgery and examined for the expression of CCN4, fibrosis, and inflammation markers. Hepatic stellate LX-2 cells were treated with human recombinant CCN4 alone or in combination with LPS or transforming growth factor beta (TGF-β) and examined for fibrosis and inflammation markers. CCN4 mRNA expression in the liver positively correlated with BMI and expression of fibrosis markers COL1A1, COL3A1, COL6A1, αSMA, TGFB1, extracellular matrix turnover enzymes TIMP1 and MMP9, and the inflammatory marker ITGAX/CD11c. In LX-2 cells, the exposure to recombinant CCN4 caused dose-dependent induction of MMP9 and MCP1. CCN4 potentiated the TGF-β-mediated induction of COL3A1, TIMP1, and MCP1 but showed no interaction with LPS treatment. Our results suggest a potential contribution of CCN4 to the early pathogenesis of obesity-associated liver fibrosis.

The role of visfatin and resistin in an in vitro model of obesity-induced invasive liver cancer

Obesity is associated with the development of liver disease and its progression to hepatocellular carcinoma. This link may be attributed to adipocytokines such as visfatin and resistin which have been shown to promote liver cancer incidence and progression. Studies have yet to determine the role of visfatin and resistin in liver cancer, specifically in the context of obesity. The objective of this study was to investigate the effect of neutralizing visfatin and resistin in obese (OB) or normal weight (NW) sera to determine the contribution of these proteins in obesity-induced invasive liver cancer. Sera from OB or NW males was used to determine the efficacy of neutralizing visfatin and resistin to reduce the obesity-induced liver cancer phenotype. HepG2 and SNU-449 cells were exposed to OB and NW sera ± antibodies for visfatin or resistin. The neutralizing antibodies differentially suppressed invasion, reactive oxygen species production, and matrix metalloproteinase-9 secretion. These changes corresponded with a decrease in phosphorylated extracellular signal-regulated kinases and protein kinase B in HepG2 cells, but differences were not observed in CAP1 or β-catenin. In conclusion, visfatin and resistin have differential roles in obesity-associated liver cancer and may be potential targets to reverse the impact of obesity on liver cancer progression.