Hepatology
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
Abstract
Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. By using microdissection and next generation RNA sequencing, we identified five genes that were most upregulated in proliferating BECs after acute injury including Mapk8ip2, Cdkn1a, Itgb6, Rgs4, and Ccl2. Immunohistochemistry analyses confirmed robust upregulation of integrin αvβ6 (ITGβ6) expression in this BEC injury model, after bile duct ligation, and in patients with chronic cholangiopathies. Deletion of Itgb6 gene attenuated BEC proliferation post-acute bile duct injury. Macrophage depletion or Ccr2-deficiency impaired ITGβ6 expression and BEC proliferation. In vitro experiments revealed that bile-acid activated monocytes promoted BEC proliferation through ITGβ6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGβ6, which work together to promote BEC proliferation, and that therefore represent potential therapeutic targets for cholangiopathies.
Authors
Adrien Guillot, Lucia Guerri, Dechun Feng, Seung-Jin Kim, Yeni Ait Ahmed, Janos Paloczi, Yong He, Kornel Schuebel, Shen Dai, Fengming Liu, Pal Pacher, Tatiana Kisseleva, Xuebin Qin, David Goldman, Frank Tacke, Bin Gao
Abstract
Sepsis is a leading cause of death in critical illness, and its pathophysiology varies depending on preexisting medical conditions. Here we identified nonalcoholic fatty liver disease (NAFLD) as an independent risk factor for sepsis in a large clinical cohort and showed a link between mortality in NAFLD-associated sepsis and hepatic mitochondrial and energetic metabolism dysfunction. Using in vivo and in vitro models of liver lipid overload, we discovered a metabolic coordination between hepatocyte mitochondria and liver macrophages that express triggering receptor expressed on myeloid cells-2 (TREM2). Trem2-deficient macrophages released exosomes that impaired hepatocytic mitochondrial structure and energy supply because of their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2). In a mouse model of NAFLD-associated sepsis, TREM2 deficiency accelerated the initial progression of NAFLD and subsequent susceptibility to sepsis. Conversely, overexpression of TREM2 in liver macrophages improved hepatic energy supply and sepsis outcome. This study demonstrates that NAFLD is a risk factor for sepsis, providing a basis for precision treatment, and identifies hepatocyte-macrophage metabolic coordination and TREM2 as potential targets for future clinical trials.
Authors
Jinchao Hou, Jue Zhang, Ping Cui, Yingyue Zhou, Can Liu, Xiaoliang Wu, Yun Ji, Sicong Wang, Baoli Cheng, Hui Ye, Liqi Shu, Kai Zhang, Di Wang, Jielin Xu, Qiang Shu, Marco Colonna, Xiangming Fang
Abstract
Monocyte homing to the liver and adhesion to the liver sinusoidal endothelial cells (LSEC) are key elements in nonalcoholic steatohepatitis (NASH) pathogenesis. We reported previously that vascular cell adhesion molecule 1 (VCAM-1) mediates monocyte adhesion to LSEC. However, the pathogenic role of VCAM-1 in NASH is unclear. Herein, we report that VCAM-1 was a top upregulated adhesion molecule in the NASH mouse liver transcriptome. Open chromatin landscape profiling combined with genome-wide transcriptome analysis showed robust transcriptional upregulation of LSEC-VCAM-1 in murine NASH. Moreover, LSEC-VCAM-1 expression was significantly increased in human NASH. LSEC-VCAM-1 expression was upregulated by palmitate treatment in vitro, and reduced with inhibition of the mitogen-activated protein 3 kinase, mixed lineage kinase 3 (MLK3). Likewise, LSEC-VCAM-1 expression was reduced in the Mlk3-/- mice with diet-induced NASH. Furthermore, VCAM-1 neutralizing antibody or pharmacological inhibition attenuated diet-induced NASH in mice, mainly via reducing the proinflammatory monocyte hepatic population as examined by mass cytometry by time of flight (CyTOF). Moreover, endothelium-specific Vcam1 knockout mice were also protected against NASH. In summary, lipotoxic stress enhances the expression of LSEC-VCAM-1, in part, through MLK3 signaling. Inhibition of VCAM-1 was salutary in murine NASH, and might serve as a potential therapeutic strategy for human NASH.
Authors
Kunimaro Furuta, Qianqian Guo, Kevin D. Pavelko, Jeong-Heon Lee, Keith D. Robertson, Yasuhiko Nakao, Jan Melek, Vijay H. Shah, Petra Hirsova, Samar H. Ibrahim
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)