Molecular mechanisms of non-alcoholic fatty liver disease development

The liver plays a key role in maintaining energy homeostasis by sensing and responding to changes in nutrient status under various metabolic conditions. Recently highlighted as a major endocrine organ, the contribution of the liver to systemic glucose and lipid metabolism is primarily attributed to signaling crosstalk between multiple organs via hepatic hormones, cytokines, and hepatokines. Hepatokines are hormone-like proteins secreted by hepatocytes, and a number of these have been associated with extra-hepatic metabolic regulation. Mounting evidence has revealed that the secretory profiles of hepatokines are significantly altered in non-alcoholic fatty liver disease (NAFLD), the most common hepatic manifestation, which frequently precedes other metabolic disorders, including insulin resistance and type 2 diabetes. Therefore, deciphering the mechanism of hepatokine-mediated inter-organ communication is essential for understanding the complex metabolic network between tissues, as well as for the identification of novel diagnostic and/or therapeutic targets in metabolic disease. In this review, we describe the hepatokine-driven inter-organ crosstalk in the context of liver pathophysiology, with a particular focus on NAFLD progression. Moreover, we summarize key hepatokines and their molecular mechanisms of metabolic control in non-hepatic tissues, discussing their potential as novel biomarkers and therapeutic targets in the treatment of metabolic diseases.

Download Full-text

Cholecystectomy as a risk factor for non-alcoholic fatty liver disease development

HPB ◽

10.1016/j.hpb.2020.07.011 ◽

2020 ◽

Vol 22 (11) ◽

pp. 1513-1520

Author(s):

Itzayana Rodríguez-Antonio ◽

Guillermo N. López-Sánchez ◽

Victor Y. Garrido-Camacho ◽

Misael Uribe ◽

Norberto C. Chávez-Tapia ◽

...

Keyword(s):

Risk Factor ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Disease Development ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Download Full-text

Polycystic ovary syndrome with feasible equivalence to overweight as a risk factor for non-alcoholic fatty liver disease development and severity in Mexican population

Annals of Hepatology ◽

10.1016/j.aohep.2020.01.004 ◽

2020 ◽

Vol 19 (3) ◽

pp. 251-257

Author(s):

Nicolás Salva-Pastor ◽

Guillermo Nahúm López-Sánchez ◽

Norberto Carlos Chávez-Tapia ◽

Jorge Román Audifred-Salomón ◽

Danniela Niebla-Cárdenas ◽

...

Keyword(s):

Risk Factor ◽

Liver Disease ◽

Polycystic Ovary Syndrome ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Polycystic Ovary ◽

Disease Development ◽

Ovary Syndrome ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Download Full-text

Hepatic Lipidomics and Molecular Imaging in a Murine Non-Alcoholic Fatty Liver Disease Model: Insights into Molecular Mechanisms

Biomolecules ◽

10.3390/biom10091275 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1275

Author(s):

Ricardo Rodríguez-Calvo ◽

Sara Samino ◽

Josefa Girona ◽

Neus Martínez-Micaelo ◽

Pere Ràfols ◽

...

Keyword(s):

Mass Spectrometry ◽

Adipose Tissue ◽

Liver Disease ◽

Molecular Imaging ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Tissue Imaging ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

An imbalance between hepatic fatty acid uptake and removal results in ectopic fat accumulation, which leads to non-alcoholic fatty liver disease (NAFLD). The amount and type of accumulated triglycerides seem to play roles in NAFLD progression; however, a complete understanding of how triglycerides contribute to NAFLD evolution is lacking. Our aim was to evaluate triglyceride accumulation in NAFLD in a murine model and its associations with molecular mechanisms involved in liver damage and adipose tissue-liver cross talk by employing lipidomic and molecular imaging techniques. C57BL/6J mice fed a high-fat diet (HFD) for 12 weeks were used as a NAFLD model. Standard-diet (STD)-fed animals were used as controls. Standard liver pathology was assessed using conventional techniques. The liver lipidome was analyzed by liquid chromatography–mass spectrometry (LC–MS) and laser desorption/ionization–mass spectrometry (LDI–MS) tissue imaging. Liver triglycerides were identified by MS/MS. The transcriptome of genes involved in intracellular lipid metabolism and inflammation was assessed by RT-PCR. Plasma leptin, resistin, adiponectin, and FABP4 levels were determined using commercial kits. HFD-fed mice displayed increased liver lipid content. LC–MS analyses identified 14 triglyceride types that were upregulated in livers from HFD-fed animals. Among these 14 types, 10 were identified in liver cross sections by LDI–MS tissue imaging. The accumulation of these triglycerides was associated with the upregulation of lipogenesis and inflammatory genes and the downregulation of β-oxidation genes. Interestingly, the levels of plasma FABP4, but not of other adipokines, were positively associated with 8 of these triglycerides in HFD-fed mice but not in STD-fed mice. Our findings suggest a putative role of FABP4 in the liver-adipose tissue cross talk in NAFLD.

Download Full-text

Integrated Bioinformatics Analysis Reveals Potential Mechanisms Associated with Intestinal Flora Intervention in Non-alcoholic Fatty Liver Disease

10.21203/rs.3.rs-112110/v1 ◽

2020 ◽

Author(s):

Yingying Liu ◽

Xinkui Liu ◽

Wei Zhou ◽

Jingyuan Zhang ◽

Siyu Guo ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Signaling Pathway ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Intestinal Flora ◽

Global Public Health ◽

Alcoholic Fatty Liver ◽

Key Genes ◽

Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease that imposes a huge economic burden on global public health. And the gut-liver axis theory supports the therapeutic role of intestinal flora in the development and progression of NAFLD. To this end, we designed bioinformatics study on the relationship between intestinal flora disorder and NAFLD, so as to explore the molecular mechanism of intestinal flora interfering with NAFLD. Methods Differentially expressed genes for NAFLD were obtained from GEO database. And the disease genes for NAFLD and intestinal flora disorder were obtained from the disease databases. Using string 11.0 database to establish protein-protein interaction network relationship and cytoscape 3.7.2 software visualization. Cytoscape plug-in MCODE and cytoHubba were used to screen the potential genes of intestinal flora disorder and NAFLD, so as to obtain potential targets for intestinal flora to interfere in the occurrence and process of NAFLD. Enrichment analysis of potential targets was carried out using R 4.0.2 software. Results The results showed that PTGS2, SPINK1 and C5AR1 may be the key genes for intestinal flora to interfere with NAFLD. CCL2, IL6, IL1B and FOS may be key genes for the development and progression of NAFLD. The gene function is mainly reflected in basic biological processes, including the regulation of metabolic process, epithelial development and immune influence. The pathway is mainly related to signal transduction, immune regulation and physiological metabolism. The TNF signaling pathway, AGE-RAGE signaling pathway in the diabetic activity, and NF-Kappa B signaling pathways are important pathways for intestinal flora to interfere with NAFLD. Conclusion According to the analysis results, there is a certain correlation between intestinal flora disorder and NAFLD. It is speculated that the mechanism by which intestinal flora may interfere with the occurrence and development of NAFLD is mainly related to inflammatory response and insulin resistance. Nevertheless, further research is needed to explore the specific molecular mechanisms.

Download Full-text

Deciphering non-alcoholic fatty liver disease through metabolomics

Biochemical Society Transactions ◽

10.1042/bst20140138 ◽

2014 ◽

Vol 42 (5) ◽

pp. 1447-1452 ◽

Cited By ~ 21

Author(s):

Ainara Cano ◽

Cristina Alonso

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Membrane Integrity ◽

Alcoholic Fatty Liver ◽

Metabolic Fluxes ◽

Starting Point ◽

Initial Symptoms ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disorders in industrialized countries. NAFLD develops in the absence of alcohol abuse and encompasses a wide spectrum of disorders ranging from benign fatty liver to non-alcoholic steatohepatitis (NASH). NASH often leads to fibrosis, cirrhosis and, finally, hepatocellular carcinoma (HCC). Therefore the earlier NAFLD is diagnosed, the better the patient's outlook. A tightly connected basic and applied research is essential to find the molecular mechanisms that accompany illness and to translate them into the clinic. From the simple starting point for triacylglycerol (TG) accumulation in the liver to the more complex implications of phospholipids in membrane biophysics, the influence of lipids may be the clue to understand NAFLD pathophysiology. Nowadays, it is achievable to diagnose non-invasively the initial symptoms to stop, revert or even prevent disease development. In this context, merging metabolomics with other techniques and the interpretation of the huge information obtained resembles the ‘Rosetta stone’ to decipher the pathological metabolic fluxes that must be targeted to find a cure. In the present review, we have tackled the application of metabolomics to find out the metabolic fluxes that underlie membrane integrity in NAFLD.

Download Full-text

Protective role of magnesium isoglycyrrhizinate in non-alcoholic fatty liver disease and the associated molecular mechanisms

International Journal of Molecular Medicine ◽

10.3892/ijmm.2016.2603 ◽

2016 ◽

Vol 38 (1) ◽

pp. 275-282 ◽

Cited By ~ 12

Author(s):

QIAN XU ◽

JI WANG ◽

FEIFEI CHEN ◽

KAISU LIN ◽

MINGAO ZHU ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Protective Role ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease ◽

Magnesium Isoglycyrrhizinate

Download Full-text

Adipocytokine Regulation and Antiangiogenic Activity Underlie the Molecular Mechanisms of Therapeutic Effects of Phyllanthus niruri against Non-Alcoholic Fatty Liver Disease

Nutrients ◽

10.3390/nu10081057 ◽

2018 ◽

Vol 10 (8) ◽

pp. 1057 ◽

Cited By ~ 2

Author(s):

Raghdaa Al Zarzour ◽

Mohammed Alshawsh ◽

Muhammad Asif ◽

Majed Al-Mansoub ◽

Zahurin Mohamed ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Therapeutic Effects ◽

Phyllanthus Niruri ◽

Antiangiogenic Effect ◽

Alcoholic Fatty Liver ◽

Antiangiogenic Activity ◽

Alcoholic Fatty Liver Disease

The growth of adipose tissues is considered angiogenesis-dependent during non-alcoholic fatty liver disease (NAFLD). We have recently reported that our standardized 50% methanolic extract (ME) of Phyllanthus niruri (50% ME of P. niruri) has alleviated NAFLD in Sprague–Dawley rats. This study aimed to assess the molecular mechanisms of action, and to further evaluate the antiangiogenic effect of this extract. NAFLD was induced by eight weeks of high-fat diet, and treatment was applied for four weeks. Antiangiogenic activity was assessed by aortic ring assay and by in vitro tests. Our findings demonstrated that the therapeutic effects of 50% ME among NAFLD rats, were associated with a significant increase in serum adiponectin, reduction in the serum levels of RBP4, vaspin, progranulin, TNF-α, IL-6, and significant downregulation of the hepatic gene expression of PPARγ, SLC10A2, and Collα1. Concomitantly, 50% ME of P. niruri has exhibited a potent antiangiogenic activity on ring assay, cell migration, vascular endothelial growth factor (VEGF), and tube formation, without any cytotoxic effect. Together, our findings revealed that the protective effects of P. niruri against NAFLD might be attributed to its antiangiogenic effect, as well as to the regulation of adipocytokines and reducing the expression of adipogenic genes.

Download Full-text