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14 pages, 4078 KiB

Open AccessArticle

Interleukin-19 Gene-Deficient Mice Promote Liver Fibrosis via Enhanced TGF-β Signaling, and the Interleukin-19-CCL2 Axis Is Important in the Direction of Liver Fibrosis

by Naoshige Ono, Takashi Fujita, Mariko Miki, Kazuhiro Nishiyama, Takeshi Izawa, Tomoko Aoyama, Mitsuru Kuwamura, Hideki Fujii and Yasu-Taka Azuma

Biomedicines 2023, 11(7), 2064; https://doi.org/10.3390/biomedicines11072064 - 22 Jul 2023

Cited by 1 | Viewed by 1797

Abstract

IL-19 is a cytokine discovered by homologous searching with IL-10 and is produced by non-immune cells, such as keratinocytes, in addition to immune cells, such as macrophages. Liver fibrosis results from the inflammation and activation of hepatic stellate cells via chronic liver injury. [...] Read more.

IL-19 is a cytokine discovered by homologous searching with IL-10 and is produced by non-immune cells, such as keratinocytes, in addition to immune cells, such as macrophages. Liver fibrosis results from the inflammation and activation of hepatic stellate cells via chronic liver injury. However, the participation of IL-19 in liver fibrosis remains to be sufficiently elucidated. Our group studied the immunological function of IL-19 in a mouse model of carbon tetrachloride (CCl₄)-induced liver fibrosis. IL-19 gene-deficient (KO) mice and body weight-matched wild-type (WT) mice were used. A liver fibrosis mouse model was created via CCl₄ administration (two times per week) for 8 weeks. In CCl₄-induced liver fibrosis, serum analysis revealed that IL-19 KO mice had higher ALT levels compared to WT mice. IL-19 KO mice had worse fibrosis, as assessed by morphological evaluation of total area stained positive with Azan and Masson trichrome. In addition, the expression of α-SMA was increased in liver tissues of IL-19 KO mice compared to WT mice. Furthermore, mRNA expression levels of TGF-β and α-SMA were enhanced in IL-19 KO mice compared to WT mice. In vitro assays revealed that IL-19-high expressing RAW264.7 cells inhibited the migration of NIH3T3 cells via the inhibited expression of CCL2 in the presence of CCl₄ and IL-4. These findings indicate that IL-19 plays a critical role in liver fibrosis by affecting TGF-β signaling and the migration of hepatic stellate cells during liver injury. Enhancement of the IL-19 signaling pathway is a potential treatment for liver fibrosis. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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21 pages, 7321 KiB

Open AccessArticle

The Effects of Probiotics on Small Intestinal Microbiota Composition, Inflammatory Cytokines and Intestinal Permeability in Patients with Non-Alcoholic Fatty Liver Disease

by Nurainina Ayob, Khairul Najmi Muhammad Nawawi, Mohamad Hizami Mohamad Nor, Raja Affendi Raja Ali, Hajar Fauzan Ahmad, Seok Fang Oon and Norfilza Mohd Mokhtar

Biomedicines 2023, 11(2), 640; https://doi.org/10.3390/biomedicines11020640 - 20 Feb 2023

Cited by 34 | Viewed by 5041

Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD) has soared globally. As our understanding of the disease grows, the role of the gut-liver axis (GLA) in NAFLD pathophysiology becomes more apparent. Hence, we focused mainly on the small intestinal area to explore the [...] Read more.

The prevalence of non-alcoholic fatty liver disease (NAFLD) has soared globally. As our understanding of the disease grows, the role of the gut-liver axis (GLA) in NAFLD pathophysiology becomes more apparent. Hence, we focused mainly on the small intestinal area to explore the role of GLA. We looked at how multi-strain probiotics (MCP^® BCMC^® strains) containing six different Lactobacillus and Bifidobacterium species affected the small intestinal gut microbiota, inflammatory cytokines, and permeability in NAFLD patients. After six months of supplementation, biochemical blood analysis did not show any discernible alterations in either group. Five predominant phyla known as Actinobacteria, Proteobacteria, Firmicutes, Bacteroidota and Fusobacteria were found in NAFLD patients. The probiotics group demonstrated a significant cluster formation of microbiota composition through beta-diversity analysis (p < 0.05). This group significantly reduced three unclassifiable species: unclassified_Proteobacteria, unclassified_Streptococcus, and unclassified_Stenotrophomonas. In contrast, the placebo group showed a significant increase in Prevotella_melaninogenica and Rothia_mucilaginosa, which were classified as pathogens. Real-time quantitative PCR analysis of small intestinal mucosal inflammatory cytokines revealed a significant decrease in IFN-γ (−7.9 ± 0.44, p < 0.0001) and TNF-α (−0.96 ± 0.25, p < 0.0033) in the probiotics group but an increase in IL-6 (12.79 ± 2.24, p < 0.0001). In terms of small intestinal permeability analysis, the probiotics group, unfortunately, did not show any positive changes through ELISA analysis. Both probiotics and placebo groups exhibited a significant increase in the level of circulating zonulin (probiotics: 107.6 ng/mL ± 124.7, p = 0.005 vs. placebo: 106.9 ng/mL ± 101.3, p = 0.0002) and a significant decrease in circulating zonula occluden-1 (ZO-1) (probiotics: −34.51 ng/mL ± 18.38, p < 0.0001 vs. placebo: −33.34 ng/mL ± 16.62, p = 0.0001). The consumption of Lactobacillus and Bifidobacterium suggested the presence of a well-balanced gut microbiota composition. Probiotic supplementation improves dysbiosis in NAFLD patients. This eventually stabilised the expression of inflammatory cytokines and mucosal immune function. To summarise, more research on probiotic supplementation as a supplement to a healthy diet and lifestyle is required to address NAFLD and its underlying causes. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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11 pages, 423 KiB

Open AccessArticle

Dynapenia, Muscle Quality, and Hepatic Steatosis in Patients with Obesity and Sarcopenic Obesity

by Francesco Frigerio, Maria De Marinis, Francesca Camardella, Vito Cantisani, Alessandro Pinto, Marco Bernardi, Carla Lubrano, Lucio Gnessi, Massimo Federici, Lorenzo Maria Donini and Eleonora Poggiogalle

Biomedicines 2023, 11(2), 472; https://doi.org/10.3390/biomedicines11020472 - 6 Feb 2023

Cited by 1 | Viewed by 2688

Abstract

Accumulating evidence supports a connection between sarcopenic obesity (SO) and NAFLD. The extent to which fatty liver contributes to impaired muscle contractility is not yet well established. The aim of our study was to investigate the effect of NAFLD on dynapenia in patients [...] Read more.

Accumulating evidence supports a connection between sarcopenic obesity (SO) and NAFLD. The extent to which fatty liver contributes to impaired muscle contractility is not yet well established. The aim of our study was to investigate the effect of NAFLD on dynapenia in patients with SO. In this study, 71 non-diabetic subjects (age 55 (7.8) years, BMI 35.2 kg/m² (32.6–38.8)) were classified as having SO and non-sarcopenic obesity (NSO). SO patients displayed worse serum lipid profiles, higher body fat, and lower skeletal muscle mass (both total and appendicular) than NSO patients, despite the absence of any significant differences in body weight, glycometabolic parameters, and hepatic steatosis prevalence. A positive correlation between disposition index and muscle quality index (MQI) (r = 0.393, p = 0.013) emerged after controlling for menopause and body fat percentage. Based on multiple linear regression analysis, MQI was significantly positively associated with the disposition index (β: 0.059, SE: 0.002, p = 0.006) after adjustment for menopause, body fat percentage, and the presence of hepatic steatosis according to the hepatorenal index (HRI). Similar findings emerged when including liver enzyme levels in place of hepatic steatosis. Muscle quality was positively associated with β-cell function corrected for insulin resistance among patients with obesity and sarcopenic obesity, irrespective of the presence of fatty liver disease. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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18 pages, 2169 KiB

Open AccessArticle

Impaired Function of Solute Carrier Family 19 Leads to Low Folate Levels and Lipid Droplet Accumulation in Hepatocytes

by Ainara Cano, Mercedes Vazquez-Chantada, Javier Conde-Vancells, Aintzane Gonzalez-Lahera, David Mosen-Ansorena, Francisco J. Blanco, Karine Clément, Judith Aron-Wisnewsky, Albert Tran, Philippe Gual, Carmelo García-Monzón, Joan Caballería, Azucena Castro, María Luz Martínez-Chantar, José M. Mato, Huiping Zhu, Richard H. Finnell and Ana M. Aransay

Biomedicines 2023, 11(2), 337; https://doi.org/10.3390/biomedicines11020337 - 31 Jan 2023

Cited by 2 | Viewed by 3244

Abstract

Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (SLC19A1) was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver [...] Read more.

Low serum folate levels are inversely related to metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (SLC19A1) was assessed to clarify its involvement in lipid accumulation during the onset of MAFLD in humans and in liver cells by genomic, transcriptomic, and metabolomic techniques. Genotypes of 3 SNPs in a case-control cohort were initially correlated to clinical and serum MAFLD markers. Subsequently, the expression of 84 key genes in response to the loss of SLC19A1 was evaluated with the aid of an RT² profiler-array. After shRNA-silencing of SLC19A1 in THLE2 cells, folate and lipid levels were measured by ELISA and staining techniques, respectively. In addition, up to 482 amino acids and lipid metabolites were semi-quantified in SLC19A1-knockdown (KD) cells through ultra-high-performance liquid chromatography coupled with mass spectrometry. SNPs, rs1051266 and rs3788200, were significantly associated with the development of fatty liver for the single-marker allelic test. The minor alleles of these SNPs were associated with a 0.6/−1.67-fold decreased risk of developing MAFLD. When SLC19A1 was KD in THLE2 cells, intracellular folate content was four times lower than in wild-type cells. The lack of functional SLC19A1 provoked significant changes in the regulation of genes associated with lipid droplet accumulation within the cell and the onset of NAFLD. Metabolomic analyses showed a highly altered profile, where most of the species that accumulated in SLC19A1-KD-cells belong to the chemical groups of triacylglycerols, diacylglycerols, polyunsaturated fatty acids, and long chain, highly unsaturated cholesterol esters. In conclusion, the lack of SLC19A1 gene expression in hepatocytes affects the regulation of key genes for normal liver function, reduces intracellular folate levels, and impairs lipid metabolism, which entails lipid droplet accumulation in hepatocytes. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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12 pages, 610 KiB

Open AccessArticle

NAFLD in Polycystic Ovary Syndrome: Association with PNPLA3 and Metabolic Features

by Amanda Medeiros Recuero, Larissa Garcia Gomes, Gustavo Arantes Rosa Maciel, Fernanda de Mello Malta, Ana Paula Moreira Salles, Denise Cerqueira Paranaguá Vezozzo, Edmund Chada Baracat, João Renato Rebello Pinho, Flair José Carrilho, José Tadeu Stefano and Claudia P. Oliveira

Biomedicines 2022, 10(11), 2719; https://doi.org/10.3390/biomedicines10112719 - 27 Oct 2022

Cited by 2 | Viewed by 1694

Abstract

Background: The aim of this study was to determine the frequency of the rs738409 polymorphism in the patatin-like phospholipase domain containing 3 (PNPLA3) gene in patients with polycystic ovary syndrome (PCOS) and its impact on nonalcoholic fatty liver disease (NAFLD) risk [...] Read more.

Background: The aim of this study was to determine the frequency of the rs738409 polymorphism in the patatin-like phospholipase domain containing 3 (PNPLA3) gene in patients with polycystic ovary syndrome (PCOS) and its impact on nonalcoholic fatty liver disease (NAFLD) risk and severity. We also evaluated other risk factors associated with NAFLD and advanced fibrosis. Methods: This was a cross-sectional study involving 163 patients with PCOS at a tertiary center. Genotyping for the PNPLA3 polymorphism was undertaken using a TaqMan assay. The degree of fibrosis was defined by transient elastography. Results: The prevalence of NAFLD was 72.4%, and the polymorphism was heterozygous in 41.7% and homozygous in 8% of patients. Homeostasis model assessment of insulin resistance ≥ 2.5 was the main factor associated with the risk of developing NAFLD (OR = 4.313, p = 0.022), and its effect was amplified by the polymorphism (OR = 12.198, p = 0.017). Age > 32 years also conferred a higher risk for NAFLD. HDL values ≥ 50 mg/dL conferred protection against the outcome. Metabolic syndrome (OR = 13.030, p = 0.020) and AST > 32 U/L (OR = 9.039, p = 0.009) were independent risk factors for advanced fibrosis. Conclusions: In women with PCOS, metabolic characteristics are more relevant than PNPLA3 polymorphism regarding the risk for NAFLD and its advanced forms, but these factors can act synergistically, increasing disease risk. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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9 pages, 850 KiB

Open AccessArticle

Waist-to-Hip Ratio and Inflammatory Parameters Are Associated with Risk of Non-Alcoholic Fatty Liver Disease in Patients with Morbid Obesity

by Marta Borges-Canha, João Sérgio Neves, Maria Manuel Silva, Fernando Mendonça, Telma Moreno, Sara Ribeiro, João Correa, Catarina Vale, Juliana Gonçalves, Helena Urbano Ferreira, Sara Gil-Santos, Vanessa Guerreiro, Ana Sande, Selma B. Souto, Jorge Pedro, Paula Freitas, Davide Carvalho and CRIO Group

Biomedicines 2022, 10(10), 2416; https://doi.org/10.3390/biomedicines10102416 - 27 Sep 2022

Cited by 9 | Viewed by 2399

Abstract

Non-alcoholic fatty liver disease (NAFLD) is associated with several other metabolic disorders, which are typically pro-inflammatory states. Body fat content is an important marker of metabolic health and abdominal fat is associated with harmful cardiometabolic outcomes. We aimed to evaluate the association between [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is associated with several other metabolic disorders, which are typically pro-inflammatory states. Body fat content is an important marker of metabolic health and abdominal fat is associated with harmful cardiometabolic outcomes. We aimed to evaluate the association between the risk of NAFLD (through Fatty Liver Index (FLI), and BMI, AST/ALT ratio, and presence of diabetes (BARD)), and anthropometric parameters, predictors of metabolic status, in patients with morbid obesity, and to evaluate the association of FLI and BARD scores with pro-inflammatory markers. We have retrospectively studied patients with morbid obesity followed in our center. In total, 2184 participants were included, with an average age of 42.8 ± 10.6 years, 84.5% being females. We report a positive association of FLI with waist circumference (β = 0.10 [0.09 to 0.11], p < 0.01) and waist-to-hip ratio (β = 8.68 [6.85 to 10.52, p < 0.01]), even after adjusting for age, sex, body mass index, diabetes, and dyslipidemia (p < 0.01 for both adjusted models). The associations of BARD with anthropometric measures were significant only in the non-adjusted model. There was a positive association between both FLI and BARD and C-reactive protein. Our results point towards a positive association between waist-to-hip ratio and the risk of hepatic steatosis, and between pro-inflammatory markers and both hepatic steatosis and fibrosis. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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13 pages, 495 KiB

Open AccessArticle

Irisin Is Related to Non-Alcoholic Fatty Liver Disease (NAFLD)

by Marcin Kosmalski, Józef Drzewoski, Izabela Szymczak-Pajor, Andrzej Zieleniak, Melania Mikołajczyk-Solińska, Jacek Kasznicki and Agnieszka Śliwińska

Biomedicines 2022, 10(9), 2253; https://doi.org/10.3390/biomedicines10092253 - 11 Sep 2022

Cited by 8 | Viewed by 2740

Abstract

Irisin is a cytokine involved in many metabolic pathways occurring, among others, in muscles, adipose tissue and liver. Thus, fluctuations in irisin levels are suggested to be related to metabolic diseases. Therefore, the purpose of our study was to evaluate whether irisin may [...] Read more.

Irisin is a cytokine involved in many metabolic pathways occurring, among others, in muscles, adipose tissue and liver. Thus, fluctuations in irisin levels are suggested to be related to metabolic diseases. Therefore, the purpose of our study was to evaluate whether irisin may be associated with non-alcoholic fatty liver disease (NAFLD). A total of 138 patients (70/68 male/female, mean age 65.61 ± 10.44 years) were enrolled in the study. The patients were assigned to the NAFLD group (n = 72, including 46 patients with type 2 diabetes (T2DM]) and the group without NAFLD (n = 66, 31 patients with T2DM). NAFLD was diagnosed based on ultrasound examination, Hepatic Steatosis Index (HSI) and Fatty Liver Index. Baseline anthropometric, blood pressure and biochemical parameters were collected. The serum irisin level was determined using an ELISA test. We observed that NAFLD was associated with an increased concentration of irisin. Moreover, Spearman correlations and linear regression analysis revealed that irisin level correlates with some anthropometric and biochemical parameters such as body mass index, glycated hemoglobin, aspartic aminotransferase, creatinine and urea. Logistic regression analysis depicted that odds for NAFLD increase 1.17 times for each 1 μg/mL rise of irisin concentration. Finally, ROC analysis showed that the concentration of irisin possesses a discriminate capacity for NAFLD and optimal cut points concentration could be designed. The risk of NAFLD in the subgroup with irisin concentration above 3.235 μg/mL was 4.57 times higher than in patients with the lower concentration of irisin. To conclude, the obtained results suggest that irisin concentration is associated with some anthropometric and biochemical parameters and should be further investigated toward its usage as a diagnostic biomarker of NAFLD. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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14 pages, 1071 KiB

Open AccessArticle

Fatty Liver as Potential Biomarker of Atherosclerotic Damage in Familial Combined Hyperlipidemia

by Giuseppe Mandraffino, Carmela Morace, Maria Stella Franzè, Veronica Nassisi, Davide Sinicropi, Maria Cinquegrani, Carlo Saitta, Riccardo Scoglio, Sebastiano Marino, Alessandra Belvedere, Valentina Cairo, Alberto Lo Gullo, Michele Scuruchi, Giovanni Raimondo and Giovanni Squadrito

Biomedicines 2022, 10(8), 1770; https://doi.org/10.3390/biomedicines10081770 - 22 Jul 2022

Cited by 8 | Viewed by 3083

Abstract

Familial combined hyperlipidemia (FCH) is a very common inherited lipid disorder, characterized by a high risk of developing cardiovascular (CV) disease and metabolic complications, including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The prevalence of non-alcoholic fatty liver disease (NAFLD) is [...] Read more.

Familial combined hyperlipidemia (FCH) is a very common inherited lipid disorder, characterized by a high risk of developing cardiovascular (CV) disease and metabolic complications, including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The prevalence of non-alcoholic fatty liver disease (NAFLD) is increased in FCH patients, especially in those with IR or T2DM. However, it is unknown how precociously metabolic and cardiovascular complications appear in FCH patients. We aimed to evaluate the prevalence of NAFLD and to assess CV risk in newly diagnosed insulin-sensitive FCH patients. From a database including 16,504 patients, 110 insulin-sensitive FCH patients were selected by general practitioners and referred to the Lipid Center. Lipid profile, fasting plasma glucose and insulin were determined by standard methods. Based on the results of the hospital screening, 96 patients were finally included (mean age 52.2 ± 9.8 years; 44 males, 52 females). All participants underwent carotid ultrasound to assess carotid intima media thickness (cIMT), presence or absence of plaque, and pulse wave velocity (PWV). Liver steatosis was assessed by both hepatic steatosis index (HSI) and abdomen ultrasound (US). Liver fibrosis was non-invasively assessed by transient elastography (TE) and by fibrosis 4 score (FIB-4) index. Carotid plaque was found in 44 out of 96 (45.8%) patients, liver steatosis was found in 68 out of 96 (70.8%) and in 41 out of 96 (42.7%) patients by US examination and HSI, respectively. Overall, 72 subjects (75%) were diagnosed with steatosis by either ultrasound or HSI, while 24 (25%) had steatosis excluded (steatosis excluded by both US and HSI). Patients with liver steatosis had a significantly higher body mass index (BMI) compared to those without (p < 0.05). Steatosis correlated with fasting insulin (p < 0.05), liver stiffness (p < 0.05), BMI (p < 0.001), and inversely with high-density lipoprotein cholesterol (p < 0.05). Fibrosis assessed by TE was significantly associated with BMI (p < 0.001) and cIMT (p < 0.05); fibrosis assessed by FIB-4 was significantly associated with sex (p < 0.05), cIMT (p < 0.05), and atherosclerotic plaque (p < 0.05). The presence of any grade of liver fibrosis was significantly associated with atherosclerotic plaque in the multivariable model, independent of alcohol habit, sex, HSI score, and liver stiffness by TE (OR 6.863, p < 0.001). In our cohort of newly diagnosed, untreated, insulin-sensitive FCH patients we found a high prevalence of liver steatosis. Indeed, the risk of atherosclerotic plaque was significantly increased in patients with liver fibrosis, suggesting a possible connection between liver disease and CV damage in dyslipidemic patients beyond the insulin resistance hypothesis. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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20 pages, 6176 KiB

Open AccessArticle

KHK, PNPLA3 and PPAR as Novel Targets for the Anti-Steatotic Action of Bempedoic Acid

by Ana Magdalena Velázquez, Roger Bentanachs, Aleix Sala-Vila, Iolanda Lázaro, Jose Rodríguez-Morató, Rosa María Sánchez, Juan Carlos Laguna, Núria Roglans and Marta Alegret

Biomedicines 2022, 10(7), 1517; https://doi.org/10.3390/biomedicines10071517 - 27 Jun 2022

Cited by 10 | Viewed by 3628

Abstract

Bempedoic acid (BemA) is an ATP-citrate lyase (ACLY) inhibitor used to treat hypercholesterolemia. We studied the anti-steatotic effect of BemA, and the mechanisms involved, in a model of fatty liver in female rats obtained through the administration of a high-fat diet supplemented with [...] Read more.

Bempedoic acid (BemA) is an ATP-citrate lyase (ACLY) inhibitor used to treat hypercholesterolemia. We studied the anti-steatotic effect of BemA, and the mechanisms involved, in a model of fatty liver in female rats obtained through the administration of a high-fat diet supplemented with liquid fructose (HFHFr) for three months. In the third month, a group of rats was treated with BemA (30 mg/kg/day) by gavage. Plasma analytes, liver histology, adiposity, and the expression of key genes controlling fatty acid metabolism were determined, and PPAR agonism was explored by using luciferase reporter assays. Our results showed that, compared to HFHFr, BemA-treated rats exhibited lower body weight, higher liver/body weight, and reduced hepatic steatosis. In addition to ACLY inhibition, we found three novel mechanisms that could account for the anti-steatotic effect: (1) reduction of liver ketohexokinase, leading to lower fructose intake and reduced de novo lipogenesis; (2) increased expression of patatin-like phospholipase domain-containing protein 3, a protein related to the export of liver triglycerides to blood; and (3) PPARα agonist activity, leading to increased hepatic fatty acid β-oxidation. In conclusion, BemA may represent a novel approach to treat hepatic steatosis, and therefore to avoid progression to advanced stages of non-alcoholic fatty liver disease. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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Review

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13 pages, 673 KiB

Open AccessReview

NAFLD and AATD Are Two Diseases with Unbalanced Lipid Metabolism: Similarities and Differences

by Sara Perez-Luz, Nerea Matamala, Gema Gomez-Mariano, Sabina Janciauskiene and Beatriz Martínez-Delgado

Biomedicines 2023, 11(7), 1961; https://doi.org/10.3390/biomedicines11071961 - 12 Jul 2023

Viewed by 3274

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a type of steatosis commonly associated with obesity, dyslipidemia, hypertension, and diabetes. Other diseases such as inherited alpha-1 antitrypsin deficiency (AATD) have also been related to the development of liver steatosis. The primary reasons leading to hepatic [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is a type of steatosis commonly associated with obesity, dyslipidemia, hypertension, and diabetes. Other diseases such as inherited alpha-1 antitrypsin deficiency (AATD) have also been related to the development of liver steatosis. The primary reasons leading to hepatic lipid deposits can be genetic and epigenetic, and the outcomes range from benign steatosis to liver failure, as well as to extrahepatic diseases. Progressive hepatocellular damage and dysregulated systemic immune responses can affect extrahepatic organs, specifically the heart and lungs. In this review, we discuss the similarities and differences between the molecular pathways of NAFLD and AATD, and the putative value of hepatic organoids as novel models to investigate the physio pathological mechanisms of liver steatosis. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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19 pages, 841 KiB

Open AccessReview

Nutritional Genomics in Nonalcoholic Fatty Liver Disease

by Carolina Vasconcellos, Oureana Ferreira, Marta Filipa Lopes, André Filipe Ribeiro, João Vasques and Catarina Sousa Guerreiro

Biomedicines 2023, 11(2), 319; https://doi.org/10.3390/biomedicines11020319 - 23 Jan 2023

Cited by 2 | Viewed by 3700

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the liver. NAFLD is epidemiologically associated with obesity, type 2 diabetes, and dyslipidemia. Environmental factors, such as physical inactivity and an [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic condition associated with genetic and environmental factors in which fat abnormally accumulates in the liver. NAFLD is epidemiologically associated with obesity, type 2 diabetes, and dyslipidemia. Environmental factors, such as physical inactivity and an unbalanced diet, interact with genetic factors, such as epigenetic mechanisms and polymorphisms for the genesis and development of the condition. Different genetic polymorphisms seem to be involved in this context, including variants in PNPLA3, TM6SF2, PEMT, and CHDH genes, playing a role in the disease’s susceptibility, development, and severity. From carbohydrate intake and weight loss to omega-3 supplementation and caloric restriction, different dietary and nutritional factors appear to be involved in controlling the onset and progression of NAFLD conditions influencing metabolism, gene, and protein expression. The polygenic risk score represents a sum of trait-associated alleles carried by an individual and seems to be associated with NAFLD outcomes depending on the dietary context. Understanding the exact extent to which lifestyle interventions and genetic predispositions can play a role in the prevention and management of NAFLD can be crucial for the establishment of a personalized and integrative approach to patients. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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23 pages, 987 KiB

Open AccessReview

Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review

by Siti Aishah Sulaiman, Vicneswarry Dorairaj and Muhammad Nafiz Haidi Adrus

Biomedicines 2023, 11(1), 106; https://doi.org/10.3390/biomedicines11010106 - 30 Dec 2022

Cited by 14 | Viewed by 4607

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks for the disease. NAFLD is a multi-factorial disease where the genetics, metabolic, and environmental factors interplay and modulate the disease’s development and progression. Several genetic polymorphisms have been identified and are associated with the disease risk. This mini-review discussed the NAFLD’s genetic polymorphisms and focusing on the differences in the findings between the populations (diversity), including of those reports that did not show any significant association. The challenges of genetic diversity are also summarized. Understanding the genetic contribution of NAFLD will allow for better diagnosis and management explicitly tailored for the various populations. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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14 pages, 346 KiB

Open AccessReview

The Role of STAMP2 in Pathogenesis of Chronic Diseases Focusing on Nonalcoholic Fatty Liver Disease: A Review

by Hye Young Kim and Young Hyun Yoo

Biomedicines 2022, 10(9), 2082; https://doi.org/10.3390/biomedicines10092082 - 26 Aug 2022

Viewed by 1927

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a major health issue. NAFLD can progress from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis or hepatocellular carcinoma. Unfortunately, there is no currently approved pharmacologic therapy for NAFLD patients. The six transmembrane [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is a major health issue. NAFLD can progress from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis or hepatocellular carcinoma. Unfortunately, there is no currently approved pharmacologic therapy for NAFLD patients. The six transmembrane protein of prostate 2 (STAMP2), a metalloreductase involved in iron and copper homeostasis, is well known for its critical role in the coordination of glucose/lipid metabolism and inflammation in metabolic tissues. We previously demonstrated that hepatic STAMP2 could be a suitable therapeutic target for NAFLD. In this review, we discuss the emerging role of STAMP2 in the dysregulation of iron metabolism events leading to NAFLD and suggest therapeutic strategies targeting STAMP2. Full article

(This article belongs to the Special Issue Metabolic and Genetic Associated Fatty Liver Diseases)

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