Hepatology
Abstract
BACKGROUND. It is unclear whether the level of serum hepatitis B virus (HBV) DNA at baseline impacts the on-treatment risk of hepatocellular carcinoma (HCC) in HBeAg positive, non-cirrhotic patients with chronic hepatitis B (CHB). METHODS. We conducted a multicenter cohort study including 2,073 entecavir- or tenofovir-treated, HBeAg-positive, non-cirrhotic, adult CHB patients with baseline HBV DNA levels ≥5.00 log10 IU/mL at three centers in Korea between January 2007 and December 2016. We evaluated the on-treatment incidence rate of HCC by baseline HBV DNA levels. RESULTS. During a median 5.7 years of continuous antiviral treatment, 47 patients developed HCC (0.39 per 100 person-years). By Kaplan–Meier analysis, HCC risk was the lowest in those with baseline HBV DNA levels ≥8.00 log10 IU/mL, increased incrementally with decreasing viral load, and the highest with HBV DNA levels 5.00–5.99 log10 IU/mL (P<0.001). By multivariable analysis, baseline HBV DNA level was an independent factor that was inversely associated with HCC risk. Compared with HBV DNA ≥8.00 log10 IU/mL, the adjusted hazard ratios for HCC risk with HBV DNA 7.00–7.99 log10 IU/mL, 6.00–6.99 log10 IU/mL, and 5.00–5.99 log10 IU/mL were 2.48 (P=0.03), 3.69 (P=0.002), and 6.10 (P<0.001), respectively. CONCLUSION. On-treatment HCC risk increased incrementally with decreasing baseline HBV DNA levels in the range of ≥5.00 log10 IU/mL in HBeAg-positive, non-cirrhotic, adult patients with CHB. Early initiation of antiviral treatment with a high viral load (≥8.00 log10 IU/mL) may maintain the lowest risk of HCC in those patients. FUNDING. Korean Government.
Authors
Won-Mook Choi, Gi-Ae Kim, Jonggi Choi, Seungbong Han, Young-Suk Lim
Targeting hepatic kisspeptin receptor ameliorates non-alcoholic fatty liver disease in a mouse model
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common liver disease has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes and metabolic syndrome. A hallmark feature of NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism which can progress to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here we have identified that activation of the kisspeptin receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high fat diet-fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In NAFLD patients and in HFD-fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.
Authors
Stephania Guzman, Magdalena Dragan, Hyokjoon Kwon, Vanessa de Oliveira, Shivani Rao, Vrushank Bhatt, Katarzyna M. Kalemba, Ankit Shah, Vinod K. Rustgi, He Wang, Paul R. Bech, Ali Abbara, Chioma Izzi-Engbeaya, Pinelopi Manousou, Jessie Yanxiang Guo, Grace L. Guo, Sally Radovick, Waljit S. Dhillo, Fredric E. Wondisford, Andy V. Babwah, Moshmi Bhattacharya
Abstract
The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced hepatic immune cells by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial – glycosphingolipid – NKT – CCL5 axis that underlies hepatic immunity.
Authors
Joshua C. Leinwand, Bidisha Paul, Ruonan Chen, Fangxi Xu, Maria A. Sierra, Madan M. Paluru, Sumant Nanduri, Carolina G. Alcantara Hirsch, Sorin A.A. Shadaloey, Fan Yang, Salma A. Adam, Qianhao Li, Michelle Bandel, Inderdeep Gakhal, Lara Appiah, Yuqi Guo, Mridula Vardhan, Zia J. Flaminio, Emilie R. Grodman, Ari Mermelstein, Wei Wang, Brian Diskin, Berk Aykut, Mohammed Khan, Gregor Werba, Smruti Pushalkar, Mia McKinstry, Zachary Kluger, Jaimie J. Park, Brandon Hsieh, Kristen Dancel-Manning, Feng-Xia Liang, James S. Park, Anjana Saxena, Xin Li, Neil D. Theise, Deepak Saxena, George Miller
Abstract
Authors
Sophie Lotersztajn, Ariane Mallat
Abstract
BACKGROUND Hepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes.METHODS Adolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging–proton density fat fraction.RESULTS Hepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: –10.6% [95% CI: –19.1%, –2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 μIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532).CONCLUSION Our results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD.TRIAL REGISTRY ClinicalTrials.gov NCT02513121.FUNDING The Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children’s Healthcare of Atlanta and Emory University’s Children’s Clinical and Translational Discovery Core, Children’s Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.
Authors
Catherine C. Cohen, Kelvin W. Li, Adina L. Alazraki, Carine Beysen, Carissa A. Carrier, Rebecca L. Cleeton, Mohamad Dandan, Janet Figueroa, Jack Knight-Scott, Cynthia J. Knott, Kimberly P. Newton, Edna M. Nyangau, Claude B. Sirlin, Patricia A. Ugalde-Nicalo, Jean A. Welsh, Marc K. Hellerstein, Jeffrey B. Schwimmer, Miriam B. Vos
Abstract
Mutations in Dyrk1b are associated with metabolic syndrome and non-alcoholic fatty liver disease in humans. Our investigations showed that DYRK1B levels are increased in the liver of patients with non-alcoholic liver steatohepatitis (NASH) and in mice fed with a high fat/sucrose diet. Increasing Dyrk1b levels in the mouse liver enhanced de novo lipogenesis (DNL), fatty-acid uptake, and TAG secretion and caused NASH and hyperlipidemia. Conversely, knockdown of Dyrk1b was protective against high-calorie induced hepatic steatosis and fibrosis and hyperlipidemia. Mechanistically, Dyrk1b increased DNL by activating mTORC2 in a kinase independent fashion. Accordingly, the Dyrk1b-induced NASH was fully rescued when mTORC2 was genetically disrupted. The elevated DNL was associated with increased plasma membrane sn-1,2-diacylglyerol levels and increased PKCε-mediated IRKT1150 phosphorylation, which resulted in impaired activation of hepatic insulin signaling and reduced hepatic glycogen storage. These findings provide new insights into the mechanisms that underlie Dyrk1b-induced hepatic lipogenesis and hepatic insulin resistance and identify Dyrk1b as a therapeutic target for NASH and insulin resistance in the liver.
Authors
Neha Bhat, Anand Narayanan, Mohsen Fathzadeh, Mario Kahn, Dongyan Zhang, Leigh Goedeke, Arpita Neogi, Rebecca L. Cardone, Richard G. Kibbey, Carlos Fernandez-Hernando, Henry N. Ginsberg, Dhanpat Jain, Gerald Shulman, Arya Mani
Abstract
Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of chronic liver disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms of NASH progression remain incompletely understood. White adipose tissue (WAT) has emerged as an important endocrine organ and contributes not only to the initial stage of NAFLD, but also to its severity. In the current study, through transcriptomic analysis we identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice. Plasma Sparcl1 levels were similarly elevated and positively correlated with hepatic pathological features in NASH patients. Functional studies showed that both chronic injection of recombinant Sparcl1 protein and overexpression of Sparcl1 exaggerated hepatic inflammation and liver injury in mice. In contrast, genetic ablation of Sparcl1, knockdown of Sparcl1 in WAT, and treatment with a Sparcl1-neutralizing antibody dramatically alleviated diet-induced NASH pathogenesis. Mechanistically, Sparcl1 promoted the expression of C-C motif chemokine ligand 2 (CCL2) in hepatocytes through binding to Toll-like receptor 4 (TLR4) and activation of the NF-κB/p65 signaling pathway. Genetically or pharmacologically blocking the CCL2/CCR2 pathway attenuated the hepatic inflammatory response evoked by Sparcl1. Thus, our results demonstrated an important role for Sparcl1 in NASH progression, suggesting a potential target for therapeutic intervention.
Authors
Bin Liu, Liping Xiang, Jing Ji, Wei Liu, Ying Chen, Mingfeng Xia, Yuejun Liu, Wenyue Liu, Peiwu Zhu, Yi Jin, Yu Han, Jieli Lu, Xiaoying Li, Minghua Zheng, Yan Lu
Abstract
The endocannabinoid system regulates appetite and energy expenditure and inhibitors of the cannabinoid receptor-1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 receptors in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 receptors in hepatocytes did not alter the development of NAFLD in mice fed a high sucrose high fat diet or high fat diet (HFD). Similarly, deletion of CB-1 deletion specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD nor did it protect mice for carbon tetrachloride (CCl4)-induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.
Authors
Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton
Abstract
Hepatic uptake and biosynthesis of fatty acids (FA), as well as the partitioning of FA into oxidative, storage, and secretory pathways are tightly regulated processes. Dysregulation of one or more of these processes can promote excess hepatic lipid accumulation, ultimately leading to systemic metabolic dysfunction. Angiopoietin-like-4 (ANGPTL4) is a secretory protein that inhibits lipoprotein lipase (LPL) and modulates triacylglycerol (TAG) homeostasis. To understand the role of ANGPTL4 in liver lipid metabolism under normal and high-fat fed conditions, we generated hepatocyte specific Angptl4 mutant mice (Hmut). Using metabolic turnover studies, we demonstrate that hepatic Angptl4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Consequently, depletion of hepatocyte Angptl4 protects against diet-induce obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that loss of Angptl4 in hepatocytes promotes FA uptake which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits Angptl4 gene expression in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage, which likely occurs via increased HL activity. Notably, this novel inhibition strategy does not cause any of the deleterious effects previously observed with neutralizing antibodies.
Authors
Abhishek K. Singh, Balkrishna Chaube, Xinbo Zhang, Jonathan Sun, Kathryn M. Citrin, Alberto Canfrán-Duque, Binod Aryal, Noemi Rotllan, Luis Varela, Richard G. Lee, Tamas L. Horvath, Nathan Price, Yajaira Suárez, Carlos Fernandez-Hernando
Abstract
Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand these potentially opposing functions by interrogating functional relationships between CAF subtypes, their mediators, desmoplasia and tumor growth in wide range of tumor types metastasizing to the liver, the most common organ site for metastasis. Depletion of hepatic stellate cells (HSC), which represented main source of CAF in mice and patients in our study, or depletion of all CAF decreased tumor growth and mortality in desmoplastic colorectal and pancreatic metastasis, but not in non-desmoplastic metastatic tumors. Single cell RNA-sequencing in conjunction with CellPhoneDB ligand-receptor analysis, as well as studies in immune cell-depleted and HSC-selective knockout mice uncovered direct CAF-tumor interactions as tumor-promoting mechanism, mediated by myofibroblastic CAF (myCAF)-secreted hyaluronan and inflammatory CAF (iCAF)-secreted HGF. These effects were opposed by myCAF-expressed type-I collagen, which suppressed tumor growth by mechanically restraining tumor spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction by type-I collagen opposes the overall tumor-promoting effects of CAF, thus providing a mechanistic explanation for their dual functions in cancer. Therapeutic targeting of tumor-promoting CAF mediators while preserving type-I collagen may convert CAF from tumor-promoting to tumor-restricting.
Authors
Sonakshi Bhattacharjee, Florian Hamberger, Aashreya Ravichandra, Maximilian Miller, Ajay Nair, Silvia Affo, Aveline Filliol, LiKang Chin, Thomas M. Savage, Deqi Yin, Naita Maren Wirsik, Adam Mehal, Nicholas Arpaia, Ekihiro Seki, Matthias Mack, Di Zhu, Peter A. Sims, Ben Z. Stanger, Kenneth P. Olive, Thomas Schmidt, Rebecca G. Wells, Ingmar Mederacke, Robert F. Schwabe
Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)