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Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease
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Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2019) | Viewed by 101887

Special Issue Editors

Prof. Dr. Amalia Gastaldelli

grade E-Mail Website
Guest Editor
Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy
Interests: insulin resistance; hepatology; diabetes; hypertension; metabolic syndrome; glucose metabolism; fatty liver; metabolism; nutrition
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Silvia Fargion

E-Mail Website
Guest Editor
Ospedale Maggiore Policlinico Milano, Internal Medicine and Metabolic Diseases, Milan, Italy

Special Issue Information

Dear Colleagues,

The worldwide obesity epidemic has increased the incidence of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). NAFLD prevalence is now estimated to be 25% of the world population and is the most common cause of liver transplantation. Although several mechanisms have been hypothesized, further research is needed to understand genetic modifiers, natural history, and the molecular pathogenesis of NAFLD, as well as the biological mechanisms by which NAFLD progresses to non-alcoholic steatohepatitis (NASH), influences the risk of hepatocarcinoma (HCC) and extra-hepatic diseases. Furthermore, the impact of environment (e.g., exposure to bacteria, virus or pollutants) on the onset of NAFLD and metabolic abnormalities is becoming evident. 

This Special Issue of IJMS, will cover a selection of original articles and current reviews in the field of “Pathophysiological Molecular Mechanisms of Non-Alcoholic Fatty Liver Disease ".

We invite investigators to contribute either original research articles or review articles focusing on the variety of  mechanisms that either contribute to the onset and worsening of NAFLD in lean vs obese patients, in  type 2 diabetic vs non diabetics subjects and to the development of hepatocellular carcinoma in NASH.

Prof. Dr. Amalia Gastaldelli
Prof. Dr. Silvia Fargion
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Metabolic vs genetic NAFLD
  • Alterations in lipid synthesis and lipid composition
  • Ectopic fat accumulation, lipotoxicity and lipid mediated cell signaling
  • Inflammation
  • Metabolomics and lipidomics
  • Protein metabolism and sarcopenia
  • NAFLD and virus
  • Gut liver axis, gut microbiota and gut hormones
  • Bile acids
  • Mitochondrial function in NAFLD
  • Energy expenditure and Exercise
  • Food composition and different types of diets
  • Environmental factors that can promote NAFLD
  • Fibrosis in NAFLD
  • Hepatocellular carcinoma in NASH

Published Papers (15 papers)

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Research

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16 pages, 1960 KiB  
Article
Combined Treatment with L-Carnitine and Nicotinamide Riboside Improves Hepatic Metabolism and Attenuates Obesity and Liver Steatosis
by Kanita Salic, Eveline Gart, Florine Seidel, Lars Verschuren, Martien Caspers, Wim van Duyvenvoorde, Kari E. Wong, Jaap Keijer, Ivana Bobeldijk-Pastorova, Peter Y. Wielinga and Robert Kleemann
Int. J. Mol. Sci. 2019, 20(18), 4359; https://doi.org/10.3390/ijms20184359 - 05 Sep 2019
Cited by 31 | Viewed by 5424
Abstract
Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment [...] Read more.
Obesity characterized by adiposity and ectopic fat accumulation is associated with the development of non-alcoholic fatty liver disease (NAFLD). Treatments that stimulate lipid utilization may prevent the development of obesity and comorbidities. This study evaluated the potential anti-obesogenic hepatoprotective effects of combined treatment with L-carnitine and nicotinamide riboside, i.e., components that can enhance fatty acid transfer across the inner mitochondrial membrane and increase nicotinamide adenine nucleotide (NAD+) levels, which are necessary for β-oxidation and the TCA cycle, respectively. Ldlr −/−.Leiden mice were treated with high-fat diet (HFD) supplemented with L-carnitine (LC; 0.4% w/w), nicotinamide riboside (NR; 0.3% w/w) or both (COMBI) for 21 weeks. L-carnitine plasma levels were reduced by HFD and normalized by LC. NR supplementation raised its plasma metabolite levels demonstrating effective delivery. Although food intake and ambulatory activity were comparable in all groups, COMBI treatment significantly attenuated HFD-induced body weight gain, fat mass gain (−17%) and hepatic steatosis (−22%). Also, NR and COMBI reduced hepatic 4-hydroxynonenal adducts. Upstream-regulator gene analysis demonstrated that COMBI reversed detrimental effects of HFD on liver metabolism pathways and associated regulators, e.g., ACOX, SCAP, SREBF, PPARGC1B, and INSR. Combination treatment with LC and NR exerts protective effects on metabolic pathways and constitutes a new approach to attenuate HFD-induced obesity and NAFLD. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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14 pages, 11413 KiB  
Article
The Number of Liver Galectin-3 Positive Cells Is Dually Correlated with NAFLD Severity in Children
by Felipe Leite de Oliveira, Nadia Panera, Cristiano De Stefanis, Antonella Mosca, Valentina D’Oria, Annalisa Crudele, Rita De Vito, Valerio Nobili and Anna Alisi
Int. J. Mol. Sci. 2019, 20(14), 3460; https://doi.org/10.3390/ijms20143460 - 14 Jul 2019
Cited by 15 | Viewed by 4294
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a complex disease ranging from steatosis to non-alcoholic steatohepatitis (NASH). Galectin-3 (Gal-3), which is a β-galactoside binding protein, has been associated with liver fibrosis, but its role in NAFLD remains elusive. We investigated the expression of Gal-3 [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is a complex disease ranging from steatosis to non-alcoholic steatohepatitis (NASH). Galectin-3 (Gal-3), which is a β-galactoside binding protein, has been associated with liver fibrosis, but its role in NAFLD remains elusive. We investigated the expression of Gal-3 in liver resident cells and its potential association with liver damage in 40 children with biopsy-proven NAFLD. We found that several liver cells expressed Gal-3. The number of total Gal-3 positive cells decreased with the severity of disease and the cells were correlated with the presence of steatosis and the diagnosis of NASH. CD68 macrophages expressed Gal-3 but the number CD68/Gal-3 positive cells was significantly reduced in patients diagnosed with steatosis and NASH. Triple CD68/CD206/Gal-3, which represented the subpopulation of M2 macrophages, were mainly present in patients without NASH, and clearly reduced in patients with steatosis and NASH. On the contrary, the number of α-smooth muscle actin (SMA)/Gal-3 positive cells increased with the severity of fibrosis in children with NAFLD. Our data demonstrated that the number of Gal-3 positive cells was associated with tissue damage in different ways, which suggests a dual role of this protein in the pathogenesis of pediatric NAFLD, even if the role of Gal-3 deserves further studies. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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18 pages, 5549 KiB  
Article
Hepatoprotective Effect of Kombucha Tea in Rodent Model of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis
by Chanbin Lee, Jieun Kim, Sihyung Wang, Sumi Sung, Namgyu Kim, Hyun-Hee Lee, Young-Su Seo and Youngmi Jung
Int. J. Mol. Sci. 2019, 20(9), 2369; https://doi.org/10.3390/ijms20092369 - 13 May 2019
Cited by 26 | Viewed by 8534
Abstract
Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). [...] Read more.
Kombucha tea (KT) has emerged as a substance that protects the liver from damage; however, its mechanisms of action on the fatty liver remain unclear. Therefore, we investigated the potential role of KT and its underlying mechanisms on nonalcoholic fatty liver disease (NAFLD). db/db mice that were fed methionine/choline-deficient (MCD) diets for seven weeks were treated for vehicle (M + V) or KT (M + K) and fed with MCD for four additional weeks. Histomorphological injury and increased levels of liver enzymes and lipids were evident in the M + V group, whereas these symptoms were ameliorated in the M + K group. The M + K group had more proliferating and less apoptotic hepatocytic cells than the M + V group. Lipid uptake and lipogenesis significantly decreased, and free fatty acid (FFA) oxidation increased in the M + K, when compared with the M + V group. With the reduction of hedgehog signaling, inflammation and fibrosis also declined in the M + K group. Palmitate (PA) treatment increased the accumulation of lipid droplets and decreased the viability of primary hepatocytes, whereas KT suppressed PA-induced damage in these cells by enhancing intracellular lipid disposal. These results suggest that KT protects hepatocytes from lipid toxicity by influencing the lipid metabolism, and it attenuates inflammation and fibrosis, which contributes to liver restoration in mice with NAFLD. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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16 pages, 2768 KiB  
Article
Human Multilineage 3D Spheroids as a Model of Liver Steatosis and Fibrosis
by Piero Pingitore, Kavitha Sasidharan, Matias Ekstrand, Sebastian Prill, Daniel Lindén and Stefano Romeo
Int. J. Mol. Sci. 2019, 20(7), 1629; https://doi.org/10.3390/ijms20071629 - 02 Apr 2019
Cited by 78 | Viewed by 11282
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the disease progression is not clear, and there are no approved drugs to treat non-alcoholic steatohepatitis (NASH), the most [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in western countries. Despite the high prevalence of NAFLD, the underlying biology of the disease progression is not clear, and there are no approved drugs to treat non-alcoholic steatohepatitis (NASH), the most advanced form of the disease. Thus, there is an urgent need for developing advanced in vitro human cellular systems to study disease mechanisms and drug responses. We attempted to create an organoid system genetically predisposed to NAFLD and to induce steatosis and fibrosis in it by adding free fatty acids. We used multilineage 3D spheroids composed by hepatocytes (HepG2) and hepatic stellate cells (LX-2) with a physiological ratio (24:1). HepG2 and LX-2 cells are homozygotes for the PNPLA3 I148M sequence variant, the strongest genetic determinant of NAFLD. We demonstrate that hepatic stellate cells facilitate the compactness of 3D spheroids. Then, we show that the spheroids develop accumulations of fat and collagen upon exposure to free fatty acids. Finally, this accumulation was rescued by incubating spheroids with liraglutide or elafibranor, drugs that are in clinical trials for the treatment of NASH. In conclusion, we have established a simple, easy to handle, in vitro model of genetically induced NAFLD consisting of multilineage 3D spheroids. This tool may be used to understand molecular mechanisms involved in the early stages of fibrogenesis induced by lipid accumulation. Moreover, it may be used to identify new compounds to treat NASH using high-throughput drug screening. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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20 pages, 4100 KiB  
Article
Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD
by Eveline Gart, Everton Souto Lima, Frank Schuren, Christa G. F. De Ruiter, Joline Attema, Lars Verschuren, Jaap Keijer, Kanita Salic, Martine C. Morrison and Robert Kleemann
Int. J. Mol. Sci. 2019, 20(1), 1; https://doi.org/10.3390/ijms20010001 - 20 Dec 2018
Cited by 34 | Viewed by 5903
Abstract
Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host [...] Read more.
Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of microbiota changes in the ileum and colon using multiple diets and investigating both fecal and mucosal samples. Ldlr−/−.Leiden mice received one of three different energy-dense (ED)-diets (n = 15/group) for 15 weeks. All of the ED diets induced obesity and metabolic risk factors, altered short-chain fatty acids (SCFA), and increased gut permeability and NAFLD to various extents. ED diets reduced the diversity of high-abundant bacteria and increased the diversity of low-abundant bacteria in all of the gut compartments. The ED groups showed highly variable, partially overlapping microbiota compositions that differed significantly from chow. Correlation analyses demonstrated that (1) specific groups of bacteria correlate with metabolic risk factors, organ dysfunction, and NAFLD endpoints, (2) colon mucosa had greater predictive value than other compartments, (3) correlating bacteria differed per compartment, and (4) some bacteria correlated with plasma SCFA levels. In conclusion, this comprehensive microbiota analysis demonstrates correlations between the microbiota and dysfunctions of gut, adipose tissue, and liver, independent of a specific disease-inducing diet. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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14 pages, 2859 KiB  
Article
Regulation of Leptin Methylation Not via Apoptosis by Melatonin in the Rescue of Chronic Programming Liver Steatosis
by Ching-Chou Tsai, Yu-Ju Lin, Hong-Ren Yu, Jiunn-Ming Sheen, I-Chun Lin, Yun-Ju Lai, You-Lin Tain, Li-Tung Huang and Mao-Meng Tiao
Int. J. Mol. Sci. 2018, 19(11), 3565; https://doi.org/10.3390/ijms19113565 - 12 Nov 2018
Cited by 6 | Viewed by 3094
Abstract
We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14–21 were administered with intraperitoneal dexamethasone [...] Read more.
We examined the mechanisms of chronic liver steatosis after prenatal dexamethasone exposure and whether melatonin rescues adult offspring with liver steatosis. Melatonin rescued prenatal dexamethasone-exposed livers with steatosis in young rats. Sprague-Dawley rats pregnant at gestational day 14–21 were administered with intraperitoneal dexamethasone (DEX) or prenatal dexamethasone and melatonin between gestational day 14 and postnatal day ~120 (DEX+MEL). Chronic programming effects in the liver were assessed at day ~120. Liver steatosis increased in the DEX compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05), with no changes in cellular apoptosis. Expression of leptin and its receptor decreased in the DEX (p < 0.05) and increased in the DEX+MEL group (p < 0.05), as revealed by RT-PCR and Western blotting. Tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 expression increased in the DEX group compared with that in the vehicle group and decreased in the DEX+MEL group (p < 0.05). Liver DNA methyltransferase activity and leptin methylation increased in the DEX group (p < 0.05) and decreased in the DEX+MEL group (p < 0.05), with no changes in HDAC activity. Thus, prenatal dexamethasone induces liver steatosis at ~120 days via altered leptin expression and liver inflammation without leptin resistance. Melatonin reverses leptin methylation and expression and decreases inflammation and chronic liver steatosis not via apoptosis or histone deacetylation (HDAC). Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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14 pages, 2071 KiB  
Article
Hepatoprotective Effect of Loquat Leaf Flavonoids in PM2.5-Induced Non-Alcoholic Fatty Liver Disease via Regulation of IRs-1/Akt and CYP2E1/JNK Pathways
by Tunyu Jian, Xiaoqin Ding, Yuexian Wu, Bingru Ren, Weilin Li, Han Lv and Jian Chen
Int. J. Mol. Sci. 2018, 19(10), 3005; https://doi.org/10.3390/ijms19103005 - 01 Oct 2018
Cited by 44 | Viewed by 6183
Abstract
Ambient air particulate matter (PM) represents a class of heterogeneous substances present in polluted air, which contains many harmful components. Exposure to ambient particulate matter in fine rages (PM2.5) is associated with non-alcoholic fatty liver disease (NAFLD). Loquat Leaf possesses pharmacological [...] Read more.
Ambient air particulate matter (PM) represents a class of heterogeneous substances present in polluted air, which contains many harmful components. Exposure to ambient particulate matter in fine rages (PM2.5) is associated with non-alcoholic fatty liver disease (NAFLD). Loquat Leaf possesses pharmacological actions on NAFLD. As the main biological active ingredients, the potential therapeutic role of total flavonoids (TF) isolated from Loquat Leaf in PM2.5-induced NAFLD model remains unclear. The present study was designed to explore the hepatoprotective effect of TF in PM2.5-induced NAFLD mice with its related mechanisms of action. Mice were exposed to PM2.5 to induce NAFLD, and body weight, the ratio of liver to body weight, and blood lipids increased significantly compared with the control group. It was found that TF significantly reduced the above parameters in PM2.5-induced NAFLD mice. TF treatment alleviated oxidative stress by preventing the accumulation of oxidative product malondialdehyde (MDA) and by strengthening the anti-oxidative capacity of superoxide dismutase (SOD). TF was also found to reduce the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity in the PM2.5 group. In addition, TF repaired the PM2.5-induced decline of insulin receptor substrate-1 (IRs-1) and protein kinase B (Akt) phosphorylation. Meanwhile, the data showed TF suppressed the expression of cytochrome P450 2E1(CYP2E1) and the phosphorylation of c-jun N-terminal kinase (JNK) in PM2.5-induced NAFLD. Taken together, these findings show that TF alleviate PM2.5-induced NAFLD via regulation of IRs-1/Akt and CYP2E1/JNK pathways, which may have potential for further development as novel therapeutic agents for NAFLD. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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Review

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20 pages, 764 KiB  
Review
The Burden of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: Screening Issue and Future Perspectives
by Grazia Pennisi, Ciro Celsa, Antonina Giammanco, Federica Spatola and Salvatore Petta
Int. J. Mol. Sci. 2019, 20(22), 5613; https://doi.org/10.3390/ijms20225613 - 09 Nov 2019
Cited by 36 | Viewed by 4306
Abstract
In recent decades, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the Western world, and the occurrence of its complications, such as hepatocellular carcinoma (HCC), has rapidly increased. Obesity and diabetes are considered not only the main triggers [...] Read more.
In recent decades, non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the Western world, and the occurrence of its complications, such as hepatocellular carcinoma (HCC), has rapidly increased. Obesity and diabetes are considered not only the main triggers for the development of the disease, but also two independent risk factors for HCC. Single nucleotide polymorphisms (such as PNPLA3, TM6SF2 and MBOAT7) are related to the susceptibility to the development of HCC and its progression. Therefore, an appropriate follow-up of these patients is needed for the early diagnosis and treatment of HCC. To date, international guidelines recommend the use of ultrasonography with or without alpha-fetoprotein (AFP) in patients with advanced fibrosis. Furthermore, the use of non-invasive tools could represent a strategy to implement surveillance performance. In this review, we analyzed the main risk factors of NAFLD-related HCC, the validated screening methods and the future perspectives. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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19 pages, 3249 KiB  
Review
Development and Progression of Non-Alcoholic Fatty Liver Disease: The Role of Advanced Glycation End Products
by Dinali H. Fernando, Josephine M. Forbes, Peter W. Angus and Chandana B. Herath
Int. J. Mol. Sci. 2019, 20(20), 5037; https://doi.org/10.3390/ijms20205037 - 11 Oct 2019
Cited by 97 | Viewed by 8892
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population and is now a major cause of liver disease-related premature illness and deaths in the world. Treatment is largely based on lifestyle modification, which is difficult to achieve in most [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population and is now a major cause of liver disease-related premature illness and deaths in the world. Treatment is largely based on lifestyle modification, which is difficult to achieve in most patients. Progression of simple fatty liver or steatosis to its severe form non-alcoholic steatohepatitis (NASH) and liver fibrosis has been explained by a ‘two-hit hypothesis’. Whilst simple steatosis is considered the first hit, its transformation to NASH may be driven by a second hit. Of several factors that constitute the second hit, advanced glycation end products (AGEs), which are formed when reducing-sugars react with proteins or lipids, have been implicated as major candidates that drive steatosis to NASH via the receptor for AGEs (RAGE). Both endogenous and processed food-derived (exogenous) AGEs can activate RAGE, mainly present on Kupffer cells and hepatic stellate cells, thus propagating NAFLD progression. This review focuses on the pathophysiology of NAFLD with special emphasis on the role of food-derived AGEs in NAFLD progression to NASH and liver fibrosis. Moreover, the effect of dietary manipulation to reduce AGE content in food or the therapies targeting AGE/RAGE pathway on disease progression is also discussed. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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22 pages, 1065 KiB  
Review
Paraoxonase-1 as a Regulator of Glucose and Lipid Homeostasis: Impact on the Onset and Progression of Metabolic Disorders
by Maria João Meneses, Regina Silvestre, Inês Sousa-Lima and Maria Paula Macedo
Int. J. Mol. Sci. 2019, 20(16), 4049; https://doi.org/10.3390/ijms20164049 - 19 Aug 2019
Cited by 58 | Viewed by 6399
Abstract
Metabolic disorders are characterized by an overall state of inflammation and oxidative stress, which highlight the importance of a functional antioxidant system and normal activity of some endogenous enzymes, namely paraoxonase-1 (PON1). PON1 is an antioxidant and anti-inflammatory glycoprotein from the paraoxonases family. [...] Read more.
Metabolic disorders are characterized by an overall state of inflammation and oxidative stress, which highlight the importance of a functional antioxidant system and normal activity of some endogenous enzymes, namely paraoxonase-1 (PON1). PON1 is an antioxidant and anti-inflammatory glycoprotein from the paraoxonases family. It is mainly expressed in the liver and secreted to the bloodstream, where it binds to HDL. Although it was first discovered due to its ability to hydrolyze paraoxon, it is now known to have an antiatherogenic role. Recent studies have shown that PON1 plays a protective role in other diseases that are associated with inflammation and oxidative stress, such as Type 1 and Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease. The aim of this review is to elucidate the physiological role of PON1, as well as the impact of altered PON1 levels in metabolic disorders. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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34 pages, 570 KiB  
Review
NAFLD in Some Common Endocrine Diseases: Prevalence, Pathophysiology, and Principles of Diagnosis and Management
by Amedeo Lonardo, Alessandro Mantovani, Simonetta Lugari and Giovanni Targher
Int. J. Mol. Sci. 2019, 20(11), 2841; https://doi.org/10.3390/ijms20112841 - 11 Jun 2019
Cited by 71 | Viewed by 7038
Abstract
Secondary nonalcoholic fatty liver disease (NAFLD) defines those complex pathophysiological and clinical consequences that ensue when the liver becomes an ectopic site of lipid storage owing to reasons other than its mutual association with the metabolic syndrome. Disorders affecting gonadal hormones, thyroid hormones, [...] Read more.
Secondary nonalcoholic fatty liver disease (NAFLD) defines those complex pathophysiological and clinical consequences that ensue when the liver becomes an ectopic site of lipid storage owing to reasons other than its mutual association with the metabolic syndrome. Disorders affecting gonadal hormones, thyroid hormones, or growth hormones (GH) may cause secondary forms of NAFLD, which exhibit specific pathophysiologic features and, in theory, the possibility to receive an effective treatment. Here, we critically discuss epidemiological and pathophysiological features, as well as principles of diagnosis and management of some common endocrine diseases, such as polycystic ovary syndrome (PCOS), hypothyroidism, hypogonadism, and GH deficiency. Collectively, these forms of NAFLD secondary to specific endocrine derangements may be envisaged as a naturally occurring disease model of NAFLD in humans. Improved understanding of such endocrine secondary forms of NAFLD promises to disclose novel clinical associations and innovative therapeutic approaches, which may potentially be applied also to selected cases of primary NAFLD. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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15 pages, 478 KiB  
Review
Cardio-Metabolic Disorders in Non-Alcoholic Fatty Liver Disease
by Hamza El Hadi, Angelo Di Vincenzo, Roberto Vettor and Marco Rossato
Int. J. Mol. Sci. 2019, 20(9), 2215; https://doi.org/10.3390/ijms20092215 - 06 May 2019
Cited by 39 | Viewed by 6719
Abstract
With the progressive epidemics of obesity, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in adults and children. The increasing prevalence and incidence of NAFLD with advanced fibrosis is concerning because patients appear to experience higher [...] Read more.
With the progressive epidemics of obesity, non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in adults and children. The increasing prevalence and incidence of NAFLD with advanced fibrosis is concerning because patients appear to experience higher non-liver-related morbidity and mortality than the general population. Recent clinical evidence suggests that NAFLD is directly associated with an increased risk of cardio-metabolic disorders. This mini review describes briefly the current understanding of the pathogenesis of NAFLD, summarizing the link between NAFLD and cardio-metabolic complications, focusing mainly upon ischemic stroke, type 2 diabetes mellitus (DM), hypertension, chronic kidney disease (CKD) and cardiac arrhythmias. In addition, it describes briefly the current understanding of the pathogenesis of NAFLD. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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33 pages, 725 KiB  
Review
Pathophysiological, Molecular and Therapeutic Issues of Nonalcoholic Fatty Liver Disease: An Overview
by Simona Marchisello, Antonino Di Pino, Roberto Scicali, Francesca Urbano, Salvatore Piro, Francesco Purrello and Agata Maria Rabuazzo
Int. J. Mol. Sci. 2019, 20(8), 1948; https://doi.org/10.3390/ijms20081948 - 20 Apr 2019
Cited by 129 | Viewed by 11088
Abstract
Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible [...] Read more.
Nonalcoholic Fatty Liver Disease (NAFLD) represents the leading cause of liver disease in developed countries but its diffusion is currently also emerging in Asian countries, in South America and in other developing countries. It is progressively becoming one of the main diseases responsible for hepatic insufficiency, hepatocarcinoma and the need for orthotopic liver transplantation. NAFLD is linked with metabolic syndrome in a close and bidirectional relationship. To date, NAFLD is a diagnosis of exclusion, and liver biopsy is the gold standard for diagnosis. NAFLD pathogenesis is complex and multifactorial, mainly involving genetic, metabolic and environmental factors. New concepts are constantly arising in the literature promising new diagnostic and therapeutic tools. One of the challenges will be to better characterize not only NAFLD development but overall NAFLD progression, in order to better identify NAFLD patients at higher risk of metabolic, cardiovascular and neoplastic complications. This review analyses NAFLD epidemiology and the different prevalence of the disease in distinct groups, particularly according to sex, age, body mass index, type 2 diabetes and dyslipidemia. Furthermore, the work expands on the pathophysiology of NAFLD, examining multiple-hit pathogenesis and the role of different factors in hepatic steatosis development and progression: genetics, metabolic factors and insulin resistance, diet, adipose tissue, gut microbiota, iron deposits, bile acids and circadian clock. In conclusion, the current available therapies for NAFLD will be discussed. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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27 pages, 1126 KiB  
Review
Mitogen Activated Protein Kinases in Steatotic and Non-Steatotic Livers Submitted to Ischemia-Reperfusion
by Mónica B. Jiménez-Castro, María Eugenia Cornide-Petronio, Jordi Gracia-Sancho, Araní Casillas-Ramírez and Carmen Peralta
Int. J. Mol. Sci. 2019, 20(7), 1785; https://doi.org/10.3390/ijms20071785 - 10 Apr 2019
Cited by 26 | Viewed by 4330
Abstract
We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of [...] Read more.
We analyzed the participation of mitogen-activated protein kinases (MAPKs), namely p38, JNK and ERK 1/2 in steatotic and non-steatotic livers undergoing ischemia-reperfusion (I-R), an unresolved problem in clinical practice. Hepatic steatosis is a major risk factor in liver surgery because these types of liver tolerate poorly to I-R injury. Also, a further increase in the prevalence of steatosis in liver surgery is to be expected. The possible therapies based on MAPK regulation aimed at reducing hepatic I-R injury will be discussed. Moreover, we reviewed the relevance of MAPK in ischemic preconditioning (PC) and evaluated whether MAPK regulators could mimic its benefits. Clinical studies indicated that this surgical strategy could be appropriate for liver surgery in both steatotic and non-steatotic livers undergoing I-R. The data presented herein suggest that further investigations are required to elucidate more extensively the mechanisms by which these kinases work in hepatic I-R. Also, further researchers based in the development of drugs that regulate MAPKs selectively are required before such approaches can be translated into clinical liver surgery. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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24 pages, 732 KiB  
Review
miRNA Signature in NAFLD: A Turning Point for a Non-Invasive Diagnosis
by Paola Dongiovanni, Marica Meroni, Miriam Longo, Silvia Fargion and Anna Ludovica Fracanzani
Int. J. Mol. Sci. 2018, 19(12), 3966; https://doi.org/10.3390/ijms19123966 - 10 Dec 2018
Cited by 92 | Viewed by 7262
Abstract
Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) defines a wide pathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) which may predispose to liver cirrhosis and hepatocellular carcinoma. It represents the leading cause of hepatic damage worldwide. Diagnosis of NASH still requires liver biopsy but due to the high prevalence of NAFLD, this procedure, which is invasive, is not practicable for mass screening. Thus, it is crucial to non-invasively identify NAFLD patients at higher risk of progression to NASH and fibrosis. It has been demonstrated that hepatic fat content and progressive liver damage have a strong heritable component. Therefore, genetic variants associated with NAFLD have been proposed as non-invasive markers to be used in clinical practice. However, genetic variability is not completely explained by these common variants and it is possible that many of the phenotypic differences result from gene-environment interactions. Indeed, NAFLD development and progression is also modulated by epigenetic factors, in particular microRNAs (miRNAs), which control at post-transcriptional level many complementary target mRNAs and whose dysregulation has been shown to have high prognostic and predictive value in NAFLD. The premise of the current review is to discuss the role of miRNAs as pathogenic factors, risk predictors and therapeutic targets in NAFLD. Full article
(This article belongs to the Special Issue Pathophysiological and Molecular Mechanisms in Non-alcoholic Fatty Liver Disease)
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