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.

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Population Study on the Impact Food Chemical Composition on Patients with Non-Alcoholic Fatty Liver Diseases

Revista de Chimie ◽

10.37358/rc.18.4.6237 ◽

2018 ◽

Vol 69 (4) ◽

pp. 961-964

Author(s):

Andrei Vasile Olteanu ◽

Georgiana Emmanuela Gilca Blanariu ◽

Gheorghe Gh. Balan ◽

Dana Elena Mitrica ◽

Elena Gologan ◽

...

Keyword(s):

Chemical Composition ◽

Fatty Liver ◽

Nutritional Value ◽

Liver Steatosis ◽

Saturated Fat ◽

Control Group ◽

Healthy Population ◽

Alcoholic Fatty Liver ◽

Major Interest ◽

The Impact

Non-alcoholic fatty liver disease (NAFLD) has become of major interest worldwide, it is estimated that more than 20% of the general population suffer from liver steatosis. NAFLD is highly associated with metabolic risk factors like type 2 diabetes mellitus, obesity and dyslipidemia, the patients diagnosed with NAFLD should adopt a high fiber low calorie diet, with reduced saturated fat and carbohydrates content, leading to weight loss and improvement of metabolic profile. Our study is aiming to shape the profile of the patient interested in being informed related to food quality and chemical composition and to evaluate the aspects on the food products label which are important for the customer. Between June 2017 and December 2017, 83 patients diagnosed with NASH were included in the study, representing the study group, while 33 subjects, without metabolic syndrome or digestive diseases, selected from patient list belonging to two general practitioners, constituted the control group. Related to the interest of being informed about the chemical composition and nutritional value of the products bought, the study showed a low interest for the provided information on nutritional value. lack of confidence in the provided information and complexity of the information are understandable, the high number of subject reasoning through lack of immediate clinical benefit is surprising. Among the healthy population the willingness to pay attention to this aspect is extremely low.

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Insights into the Impact of Microbiota in the Treatment of NAFLD/NASH and Its Potential as a Biomarker for Prognosis and Diagnosis

Biomedicines ◽

10.3390/biomedicines9020145 ◽

2021 ◽

Vol 9 (2) ◽

pp. 145

Author(s):

Julio Plaza-Díaz ◽

Patricio Solis-Urra ◽

Jerónimo Aragón-Vela ◽

Fernando Rodríguez-Rodríguez ◽

Jorge Olivares-Arancibia ◽

...

Keyword(s):

Gut Microbiota ◽

Fecal Microbiota Transplantation ◽

Liver Steatosis ◽

Intestinal Barrier ◽

Fecal Microbiota ◽

Current Treatment ◽

Immune Defense ◽

Alcoholic Fatty Liver ◽

The Impact

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver illness associated with obesity and metabolic disorders, such as hypertension, dyslipidemia, or type 2 diabetes mellitus. A more severe type of NAFLD, non-alcoholic steatohepatitis (NASH), is considered an ongoing global health threat and dramatically increases the risks of cirrhosis, liver failure, and hepatocellular carcinoma. Several reports have demonstrated that liver steatosis is associated with the elevation of certain clinical and biochemical markers but with low predictive potential. In addition, current imaging methods are inaccurate and inadequate for quantification of liver steatosis and do not distinguish clearly between the microvesicular and the macrovesicular types. On the other hand, an unhealthy status usually presents an altered gut microbiota, associated with the loss of its functions. Indeed, NAFLD pathophysiology has been linked to lower microbial diversity and a weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defense and inflammation via toll-like receptor signaling. Moreover, this activation of inflammation in hepatocytes induces progression from simple steatosis to NASH. In the present review, we aim to: (a) summarize studies on both human and animals addressed to determine the impact of alterations in gut microbiota in NASH; (b) evaluate the potential role of such alterations as biomarkers for prognosis and diagnosis of this disorder; and (c) discuss the involvement of microbiota in the current treatment for NAFLD/NASH (i.e., bariatric surgery, physical exercise and lifestyle, diet, probiotics and prebiotics, and fecal microbiota transplantation).

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A Role for Gut Microbiome Fermentative Pathways in Fatty Liver Disease Progression

Journal of Clinical Medicine ◽

10.3390/jcm9051369 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1369 ◽

Cited By ~ 1

Author(s):

Paula Iruzubieta ◽

Juan M. Medina ◽

Raúl Fernández-López ◽

Javier Crespo ◽

Fernando de la Cruz

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Disease Progression ◽

Gut Microbiome ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Alcohol Fermentation ◽

Alcoholic Fatty Liver ◽

Liver Disease Progression ◽

The Impact

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial disease in which environmental and genetic factors are involved. Although the molecular mechanisms involved in NAFLD onset and progression are not completely understood, the gut microbiome (GM) is thought to play a key role in the process, influencing multiple physiological functions. GM alterations in diversity and composition directly impact disease states with an inflammatory course, such as non-alcoholic steatohepatitis (NASH). However, how the GM influences liver disease susceptibility is largely unknown. Similarly, the impact of strategies targeting the GM for the treatment of NASH remains to be evaluated. This review provides a broad insight into the role of gut microbiota in NASH pathogenesis, as a diagnostic tool, and as a therapeutic target in this liver disease. We highlight the idea that the balance in metabolic fermentations can be key in maintaining liver homeostasis. We propose that an overabundance of alcohol-fermentation pathways in the GM may outcompete healthier, acid-producing members of the microbiota. In this way, GM ecology may precipitate a self-sustaining vicious cycle, boosting liver disease progression.

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Hepatoprotective effect of tumour necrosis factor α blockade in psoriatic arthritis: a cross-sectional study

Annals of the Rheumatic Diseases ◽

10.1136/ard.2009.116194 ◽

2009 ◽

Vol 69 (6) ◽

pp. 1148-1150 ◽

Cited By ~ 16

Author(s):

Michael Seitz ◽

Stephan Reichenbach ◽

Burkhard Möller ◽

Marcel Zwahlen ◽

Peter M Villiger ◽

...

Keyword(s):

Psoriatic Arthritis ◽

Liver Fibrosis ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Transient Elastography ◽

Liver Steatosis ◽

Tumour Necrosis Factor Α ◽

Factor Α ◽

The Impact ◽

Necrosis Factor

ObjectiveTo evaluate the impact of tumour necrosis factor α (TNFα) blockers on the presence of liver fibrosis in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with methotrexate (MTX).MethodsParticipants were consecutive patients with RA and PsA who had undergone MTX treatment for at least 1 year ± TNF blockade for over 6 months. Liver fibrosis was assessed using non-invasive transient elastography (FibroScan). Regression models were used to compare FibroScan values of patients with RA and patients with PsA receiving TNFα blockers with those who were not.ResultsFibroScan assessments were performed on 51 patients with RA and 43 patients with PsA. Compared to patients with RA, those with PsA were predominantly young men, received lower cumulative dosages of MTX and exhibited a higher incidence of liver steatosis and hyperlipidaemia. An abnormal result was observed in 7.1% of the anti-TNFα-naïve and in 13% of the anti-TNFα-treated patients in the RA group and in 30% of the anti-TNFα-naïve and 4.3% of the anti-TNFα-treated patients in the PsA group (OR=0.11, 95% CI 0.02 to 0.98). Results of the PsA group were robust when adjusted for baseline characteristics.ConclusionThe results suggest a protective effect of TNFα inhibitors against the development of liver fibrosis in patients with PsA.

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Common transcriptional programme of liver fibrosis in mouse genetic models and humans

10.1101/2020.11.02.364901 ◽

2020 ◽

Author(s):

Kaja Blagotinšek Cokan ◽

Žiga Urlep ◽

Miha Moškon ◽

Miha Mraz ◽

Xiang Y. Kong ◽

...

Keyword(s):

Transcription Factors ◽

Liver Fibrosis ◽

Metabolic Diseases ◽

Genetic Models ◽

Disease Stage ◽

The Novel ◽

Alcoholic Fatty Liver ◽

Metabolic Modelling ◽

Cancer Pathways ◽

Genome Scale

AbstractMultifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden of modern societies and frequently present with no clearly defined molecular biomarkers. Herein we used systems medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways. Enrichment analyses of KEGG, Reactome and TRANSFAC databases complemented with genome-scale metabolic modelling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional programme with activated ERα signalling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and immune system. The novel hallmarks of fibrosis are downregulated lipid pathways, including fatty acid, bile acid, and steroid hormone metabolism. Moreover, distinct metabolic subtypes of liver fibrosis were proposed, supported by unique enrichment of transcription factors based on the type of insult, disease stage, or sex.

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Hepatokines and Non-Alcoholic Fatty Liver Disease: Linking Liver Pathophysiology to Metabolism

Biomedicines ◽

10.3390/biomedicines9121903 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1903

Author(s):

Tae Hyun Kim ◽

Dong-Gyun Hong ◽

Yoon Mee Yang

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Metabolic Regulation ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Therapeutic Targets ◽

Signaling Crosstalk ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

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.

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Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

10.21203/rs.3.rs-30324/v2 ◽

2020 ◽

Author(s):

Guodong Zhang ◽

Xiaoli Wang ◽

Tzu-Yang Chung ◽

Weiwei Ye ◽

Lauren Hodge ◽

...

Keyword(s):

Liver Disease ◽

Carbon Tetrachloride ◽

Liver Fibrosis ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Liver Steatosis ◽

Western Diet ◽

High Dose ◽

Entire Study ◽

Alcoholic Fatty Liver

Abstract Background: Multiple murine models of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) have been established by using obesogenic diets and/or chemical induction. MS-NASH mouse (formally FATZO) is a spontaneously developed dysmetabolic strain that can progress from hepatosteatosis to moderate fibrosis when fed a western diet supplemented with 5% fructose (WDF). This study aimed to use carbon tetrachloride (CCl4) to accelerate and aggravate progression of NAFLD/NASH in MS-NASH mouse. Methods: Male MS-NASH mice at 8 weeks of age were fed WDF for the entire study. Starting at 16 weeks of age, CCl4 was intraperitoneally administered twice weekly at a dose of 0.2 mL/kg for 3 weeks or 0.08 mL/kg for 8 weeks. Obeticholic acid (OCA, 30 mg/kg, QD) was administered in both MS-NASH and C57Bl/6 mice fed WDF and treated with CCl4 (0.08 mL/kg).Results: WDF enhanced obesity and hepatosteatosis, as well as induced moderate fibrosis in MS-NASH mice similar to previous reports. Administration of CCl4 accelerated liver fibrosis with increased bridging and liver hydroxyproline contents, but had no significant impact on liver steatosis and lipid contents. High dose CCl4 caused high mortality and dramatic elevation of ALT and ASL, while low dose CCl4 resulted in a moderate elevation of ALT and AST with low mortality. Compared to C57BI/6 mice with WDF and CCl4 (0.08 mL/kg), MS-NASH mice had more prominent hepatosteatosis and fibrosis. OCA treatment significantly lowered liver triglycerides, steatosis and fibrosis in both MS-NASH and C57Bl/6 mice fed WDF with CCl4 treatment. Conclusions: CCl4 reduced induction time and exacerbated liver fibrosis in MS-NASH mice on WDF, proving a superior NASH model with more prominent liver pathology, which has been used favorably in pharmaceutical industry for testing novel NASH therapeutics.

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Diagnostic Accuracy of FibroScan and Factors Affecting Measurements

Diagnostics ◽

10.3390/diagnostics10110940 ◽

2020 ◽

Vol 10 (11) ◽

pp. 940 ◽

Cited By ~ 1

Author(s):

Satoshi Oeda ◽

Kenichi Tanaka ◽

Ayaka Oshima ◽

Yasue Matsumoto ◽

Eisaburo Sueoka ◽

...

Keyword(s):

Liver Fibrosis ◽

Liver Steatosis ◽

Liver Stiffness ◽

The Body ◽

Liver Stiffness Measurement ◽

Alcoholic Fatty Liver ◽

Factors Affecting ◽

Non Invasive ◽

Significant Difference ◽

Alcoholic Fatty Liver Disease

Evaluating liver steatosis and fibrosis is important for patients with non-alcoholic fatty liver disease. Although liver biopsy and pathological assessment is the gold standard for these conditions, this technique has several disadvantages. The evaluation of steatosis and fibrosis using ultrasound B-mode imaging is qualitative and subjective. The liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) determined using FibroScan are the evidence-based non-invasive measures of liver fibrosis and steatosis, respectively. The LSM and CAP measurements are carried out simultaneously, and the median values of more than ten valid measurements are used to quantify liver fibrosis and steatosis. Here, we demonstrate that the reliability of the LSM depends on the interquartile range to median ratio (IQR/Med), but CAP values do not depend on IQR/Med. In addition, the LSM is affected by inflammation, congestion, and cholestasis in addition to fibrosis, while CAP values are affected by the body mass index in addition to steatosis. We also show that the M probe provides higher LSM values but lower CAP values than the XL probe in the same population. However, there was no statistically significant difference between the diagnostic accuracies of the two probes. These findings are important to understand the reliability of FibroScan measurements and the factors influencing measurement values for all patients.

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Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr−/− mice

Proceedings of The Nutrition Society ◽

10.1017/s002966511500244x ◽

2015 ◽

Vol 75 (1) ◽

pp. 1-9 ◽

Cited By ~ 20

Author(s):

Donald B. Jump ◽

Christopher M. Depner ◽

Sasmita Tripathy ◽

Kelli A. Lytle

Keyword(s):

Oxidative Stress ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Hepatic Injury ◽

Liver Steatosis ◽

Primary Hepatocellular Carcinoma ◽

Alcoholic Fatty Liver ◽

The Impact ◽

Alcoholic Fatty Liver Disease

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity and is now the most common chronic liver disease in developed countries. NAFLD is defined as excessive accumulation of lipid in the liver, i.e. hepatosteatosis. The severity of NAFLD ranges from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH). Simple steatosis is relatively benign until it progresses to NASH, which is characterised by hepatic injury, inflammation, oxidative stress and fibrosis. Hepatic fibrosis is a risk factor for cirrhosis and primary hepatocellular carcinoma. Our studies have focused on the impact of diet on the onset and progression of NASH. We developed a mouse model of NASH by feeding Ldlr−/− mice a western diet (WD), a diet moderately high in saturated and trans-fat, sucrose and cholesterol. The WD induced a NASH phenotype in Ldlr−/− mice that recapitulates many of the clinical features of human NASH. We also assessed the capacity of the dietary n-3 PUFA, i.e. EPA (20 : 5,n-3) and DHA (22 : 6,n-3), to prevent WD-induced NASH in Ldlr−/− mice. Histologic, transcriptomic, lipidomic and metabolomic analyses established that DHA was equal or superior to EPA at attenuating WD-induced dyslipidemia and hepatic injury, inflammation, oxidative stress and fibrosis. Dietary n-3 PUFA, however, had no significant effect on WD-induced changes in body weight, body fat or blood glucose. These studies provide a molecular and metabolic basis for understanding the strengths and weaknesses of using dietary n-3 PUFA to prevent NASH in human subjects.

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Carbon tetrachloride (CCl4) accelerated development of non-alcoholic fatty liver disease (NAFLD)/steatohepatitis (NASH) in MS-NASH mice fed western diet supplemented with fructose (WDF)

BMC Gastroenterology ◽

10.1186/s12876-020-01467-w ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Guodong Zhang ◽

Xiaoli Wang ◽

Tzu-Yang Chung ◽

Weiwei Ye ◽

Lauren Hodge ◽

...

Keyword(s):

Liver Disease ◽

Carbon Tetrachloride ◽

Liver Fibrosis ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Liver Steatosis ◽

Western Diet ◽

High Dose ◽

Entire Study ◽

Alcoholic Fatty Liver

Abstract Background Multiple murine models of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) have been established by using obesogenic diets and/or chemical induction. MS-NASH mouse (formally FATZO) is a spontaneously developed dysmetabolic strain that can progress from hepatosteatosis to moderate fibrosis when fed a western diet supplemented with 5% fructose (WDF). This study aimed to use carbon tetrachloride (CCl4) to accelerate and aggravate progression of NAFLD/NASH in MS-NASH mouse. Methods Male MS-NASH mice at 8 weeks of age were fed WDF for the entire study. Starting at 16 weeks of age, CCl4 was intraperitoneally administered twice weekly at a dose of 0.2 mL/kg for 3 weeks or 0.08 mL/kg for 8 weeks. Obeticholic acid (OCA, 30 mg/kg, QD) was administered in both MS-NASH and C57Bl/6 mice fed WDF and treated with CCl4 (0.08 mL/kg). Results WDF enhanced obesity and hepatosteatosis, as well as induced moderate fibrosis in MS-NASH mice similar to previous reports. Administration of CCl4 accelerated liver fibrosis with increased bridging and liver hydroxyproline contents, but had no significant impact on liver steatosis and lipid contents. High dose CCl4 caused high mortality and dramatic elevation of ALT and ASL, while low dose CCl4 resulted in a moderate elevation of ALT and AST with low mortality. Compared to C57BI/6 mice with WDF and CCl4 (0.08 mL/kg), MS-NASH mice had more prominent hepatosteatosis and fibrosis. OCA treatment significantly lowered liver triglycerides, steatosis and fibrosis in both MS-NASH and C57Bl/6 mice fed WDF with CCl4 treatment. Conclusions CCl4 reduced induction time and exacerbated liver fibrosis in MS-NASH mice on WDF, proving a superior NASH model with more prominent liver pathology, which has been used favorably in pharmaceutical industry for testing novel NASH therapeutics.

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