International Journal of Molecular Sciences

Research

16 pages, 9725 KiB

Open AccessArticle

Atractylodes lancea Rhizome Polysaccharide Alleviates MCD Diet-Induced NASH by Inhibiting the p53/mTOR Pathway

by Dajin Pi, Zheng Liang, Maoxing Pan, Jianwei Zhen, Chuiyang Zheng, Jinyue Pan, Wen Fan, Qingliang Song, Qinhe Yang and Yupei Zhang

Int. J. Mol. Sci. 2024, 25(20), 11112; https://doi.org/10.3390/ijms252011112 - 16 Oct 2024

Viewed by 1130

Abstract

Nonalcoholic steatohepatitis (NASH) is a form of chronic liver disease that is characterized by liver inflammation and steatosis, with possible progression to fibrosis. Currently, no drugs have been approved for the treatment of NASH. In this study, we isolated a polysaccharide from Atractylodes [...] Read more.

Nonalcoholic steatohepatitis (NASH) is a form of chronic liver disease that is characterized by liver inflammation and steatosis, with possible progression to fibrosis. Currently, no drugs have been approved for the treatment of NASH. In this study, we isolated a polysaccharide from Atractylodes lancea rhizome (AP) and established a methionine- and choline-deficient (MCD) diet -induced NASH mouse model to investigate the preventive effect and potential mechanism of AP on NASH. The results showed that AP effectively reduced liver lipid accumulation and inflammation and reduced autophagy and ferroptosis in hepatocytes, thereby preventing the development of NASH. These findings suggest that AP may be a promising natural candidate for the treatment of NASH. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 3.0)

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17 pages, 3182 KiB

Open AccessArticle

Lacticaseibacillus paracsei HY7207 Alleviates Hepatic Steatosis, Inflammation, and Liver Fibrosis in Mice with Non-Alcoholic Fatty Liver Disease

by Hyeon-Ji Kim, Hye-Jin Jeon, Dong-Gun Kim, Joo-Yun Kim, Jae-Jung Shim and Jae-Hwan Lee

Int. J. Mol. Sci. 2024, 25(18), 9870; https://doi.org/10.3390/ijms25189870 - 12 Sep 2024

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Abstract

Non-alcoholic fatty acid disease (NAFLD) is caused by a build-up of fat in the liver, inducing local inflammation and fibrosis. We evaluated the effects of probiotic lactic acid-generating bacteria (LAB) derived from a traditional fermented beverage in a mouse model of NAFLD. The [...] Read more.

Non-alcoholic fatty acid disease (NAFLD) is caused by a build-up of fat in the liver, inducing local inflammation and fibrosis. We evaluated the effects of probiotic lactic acid-generating bacteria (LAB) derived from a traditional fermented beverage in a mouse model of NAFLD. The LAB isolated from this traditional Korean beverage were screened using the human hepatic cell line HepG2, and Lactocaseibacillus paracasei HY7207 (HY7207), which was the most effective inhibitor of fat accumulation, was selected for further study. HY7207 showed stable productivity in industrial-scale culture. Whole-genome sequencing of HY7207 revealed that the genome was 2.88 Mbp long, with 46.43% GC contents and 2778 predicted protein-coding DNA sequences (CDSs). HY7207 reduced the expression of lipogenesis and hepatic apoptosis-related genes in HepG2 cells treated with palmitic acid. Furthermore, the administration of 10⁹ CFU/kg/day of HY7207 for 8 weeks to mice fed an NAFLD-inducing diet improved their physiologic and serum biochemical parameters and ameliorated their hepatic steatosis. In addition, HY7207 reduced the hepatic expression of genes important for lipogenesis (Srebp1c, Fasn, C/ebpa, Pparg, and Acaca), inflammation (Tnf, Il1b, and Ccl2), and fibrosis (Col1a1, Tgfb1, and Timp1). Finally, HY7207 affected the expression of the apoptosis-related genes Bax (encoding Bcl2 associated X, an apoptosis regulator) and Bcl2 (encoding B-cell lymphoma protein 2) in the liver. These data suggest that HY7207 consumption ameliorates NAFLD in mice through effects on liver steatosis, inflammation, fibrosis, and hepatic apoptosis. Thus, L. paracasei HY7207 may be suitable for use as a functional food supplement for patients with NAFLD. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 3.0)

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10 pages, 1877 KiB

Open AccessCommunication

Thermoneutrality Inhibits Thermogenic Markers and Exacerbates Nonalcoholic Fatty Liver Disease in Mice

by Lei Hao, Md Shahjalal Hossain Khan, Yujiao Zu, Jie Liu and Shu Wang

Int. J. Mol. Sci. 2024, 25(15), 8482; https://doi.org/10.3390/ijms25158482 - 3 Aug 2024

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Abstract

Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) affects over a third of the US population and 25% globally, with current treatments proving ineffective. This study investigates whether manipulating brown adipose tissue (BAT) and beige fat activity by housing C57BL/6J mice at thermoneutral (27 °C) or standard temperatures (22 °C) impacts NAFLD development. Male mice were fed either a chow diet (CHD) or a “fast food” diet (FFD) for 10 weeks. Mice at 27 °C had reduced food intake but increased body weight and plasma leptin levels. FFD-fed mice at 27 °C had greater liver weight (2.6 vs. 1.8 g), triglyceride content (7.6 vs. 3.9 mg/g), and hepatic steatosis compared to those at 22 °C. Gene expression of fatty acid synthase, sterol regulatory element-binding protein 1, and fatty acid translocase CD36 was elevated in FFD-fed mice at 27 °C, but not in CHD-fed mice. Thermoneutral housing also reduced expression of thermogenic markers in BAT and inguinal white adipose tissue (WAT) and caused BAT whitening. In conclusion, thermoneutrality inhibits thermogenic markers and exacerbates NAFLD. Activating BAT or promoting WAT browning via cold exposure or other stimuli may offer a strategy for managing NAFLD. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 3.0)

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17 pages, 1532 KiB

Open AccessArticle

Predicting Non-Alcoholic Steatohepatitis: A Lipidomics-Driven Machine Learning Approach

by Thomai Mouskeftara, Georgios Kalopitas, Theodoros Liapikos, Konstantinos Arvanitakis, Georgios Germanidis and Helen Gika

Int. J. Mol. Sci. 2024, 25(11), 5965; https://doi.org/10.3390/ijms25115965 - 29 May 2024

Cited by 4 | Viewed by 2162

Abstract

Nonalcoholic fatty liver disease (NAFLD), nowadays the most prevalent chronic liver disease in Western countries, is characterized by a variable phenotype ranging from steatosis to nonalcoholic steatohepatitis (NASH). Intracellular lipid accumulation is considered the hallmark of NAFLD and is associated with lipotoxicity and [...] Read more.

Nonalcoholic fatty liver disease (NAFLD), nowadays the most prevalent chronic liver disease in Western countries, is characterized by a variable phenotype ranging from steatosis to nonalcoholic steatohepatitis (NASH). Intracellular lipid accumulation is considered the hallmark of NAFLD and is associated with lipotoxicity and inflammation, as well as increased oxidative stress levels. In this study, a lipidomic approach was used to investigate the plasma lipidome of 12 NASH patients, 10 Nonalcoholic Fatty Liver (NAFL) patients, and 15 healthy controls, revealing significant alterations in lipid classes, such as glycerolipids and glycerophospholipids, as well as fatty acid compositions in the context of steatosis and steatohepatitis. A machine learning XGBoost algorithm identified a panel of 15 plasma biomarkers, including HOMA-IR, BMI, platelets count, LDL-c, ferritin, AST, FA 12:0, FA 18:3 ω3, FA 20:4 ω6/FA 20:5 ω3, CAR 4:0, LPC 20:4, LPC O-16:1, LPE 18:0, DG 18:1_18:2, and CE 20:4 for predicting steatohepatitis. This research offers insights into the connection between imbalanced lipid metabolism and the formation and progression of NAFL D, while also supporting previous research findings. Future studies on lipid metabolism could lead to new therapeutic approaches and enhanced risk assessment methods, as the shift from isolated steatosis to NASH is currently poorly understood. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 3.0)

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11 pages, 465 KiB

Open AccessArticle

Glomerular Hyperfiltration: A Marker of Fibrosis Severity in Metabolic Associated Steatotic Liver Disease in an Adult Population

by Andrea Dalbeni, Marta Garbin, Mirko Zoncapè, Sara Romeo, Filippo Cattazzo, Anna Mantovani, Annalisa Cespiati, Anna Ludovica Fracanzani, Emmanouil Tsochatzis, David Sacerdoti, Alessandro Mantovani and Rosa Lombardi

Int. J. Mol. Sci. 2023, 24(21), 15837; https://doi.org/10.3390/ijms242115837 - 31 Oct 2023

Cited by 4 | Viewed by 1926

Abstract

Glomerular hyperfiltration (GH) is an increase in the glomerular filtration rate, possibly progressing to chronic kidney disease (CKD). Metabolic-associated steatotic liver disease (MASLD) is linked to an increased risk of CKD, especially if fibrosis is present; however, the association between GH and MASLD [...] Read more.

Glomerular hyperfiltration (GH) is an increase in the glomerular filtration rate, possibly progressing to chronic kidney disease (CKD). Metabolic-associated steatotic liver disease (MASLD) is linked to an increased risk of CKD, especially if fibrosis is present; however, the association between GH and MASLD has not been explored. To evaluate GH prevalence in MASLD and its possible correlation with liver fibrosis. 772 consecutive patients with ultrasound MASLD (mean age 47.3 ± 8.9 years, 67.1% males) were enrolled. GH was defined as estimated glomerular filtration rate (eGFR) greater than the upper quartile of values in the cohort. Liver stiffness measurement (LSM) by FibroScan ≥ 7.2 kPa suggested liver fibrosis. GH was present in 20% of patients, liver fibrosis in 30%. In total, 53.4% of the cohort was obese, 40.9% hypertensive, 36.3% diabetic and 70.8% dyslipidaemic. GH patients compared to non-GH were significantly younger (38.4 ± 8.3 vs. 49.5 ± 7.7, p < 0.001), with higher prevalence of LSM > 7.2 kPa (35.5% vs. 29%, p < 0.001), without any difference in metabolic comorbidities. In multivariate analysis, age (OR 0.85, CI 95% 0.82–0.87) and significant fibrosis (OR 1.83; CI 95%1.10–3.03) remained independently associated with GH, regardless of the presence of metabolic alterations and nephrotoxic drugs. GH, an early marker of renal damage, is highly prevalent in MASLD and is associated with hepatic fibrosis. GH may be considered an early marker of both liver and renal disease and its recognition could prompt the management of risk factors aimed at preventing the progression of both hepatic and renal disease. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 3.0)

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Review

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34 pages, 3599 KiB

Open AccessReview

Underlying Mechanisms behind the Brain–Gut–Liver Axis and Metabolic-Associated Fatty Liver Disease (MAFLD): An Update

by Júlia Pauli De Cól, Enzo Pereira de Lima, Fernanda Moris Pompeu, Adriano Cressoni Araújo, Ricardo de Alvares Goulart, Marcelo Dib Bechara, Lucas Fornari Laurindo, Nahum Méndez-Sánchez and Sandra Maria Barbalho

Int. J. Mol. Sci. 2024, 25(7), 3694; https://doi.org/10.3390/ijms25073694 - 26 Mar 2024

Cited by 3 | Viewed by 3615

Abstract

Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain–gut–liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to [...] Read more.

Metabolic-associated fatty liver disease (MAFLD) includes several metabolic dysfunctions caused by dysregulation in the brain–gut–liver axis and, consequently, increases cardiovascular risks and fatty liver dysfunction. In MAFLD, type 2 diabetes mellitus, obesity, and metabolic syndrome are frequently present; these conditions are related to liver lipogenesis and systemic inflammation. This study aimed to review the connection between the brain–gut–liver axis and MAFLD. The inflammatory process, cellular alterations in hepatocytes and stellate cells, hypercaloric diet, and sedentarism aggravate the prognosis of patients with MAFLD. Thus, to understand the modulation of the physiopathology of MAFLD, it is necessary to include the organokines involved in this process (adipokines, myokines, osteokines, and hepatokines) and their clinical relevance to project future perspectives of this condition and bring to light new possibilities in therapeutic approaches. Adipokines are responsible for the activation of distinct cellular signaling in different tissues, such as insulin and pro-inflammatory cytokines, which is important for balancing substances to avoid MAFLD and its progression. Myokines improve the quantity and quality of adipose tissues, contributing to avoiding the development of MAFLD. Finally, hepatokines are decisive in improving or not improving the progression of this disease through the regulation of pro-inflammatory and anti-inflammatory organokines. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 3.0)

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37 pages, 919 KiB

Open AccessReview

Osteosarcopenia in NAFLD/MAFLD: An Underappreciated Clinical Problem in Chronic Liver Disease

by Alessandra Musio, Federica Perazza, Laura Leoni, Bernardo Stefanini, Elton Dajti, Renata Menozzi, Maria Letizia Petroni, Antonio Colecchia and Federico Ravaioli

Int. J. Mol. Sci. 2023, 24(8), 7517; https://doi.org/10.3390/ijms24087517 - 19 Apr 2023

Cited by 11 | Viewed by 4040

Abstract

Chronic liver disease (CLD), including non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), affects a significant portion of the population worldwide. NAFLD is characterised by fat accumulation in the liver, while NASH is associated with inflammation and liver damage. [...] Read more.

Chronic liver disease (CLD), including non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), affects a significant portion of the population worldwide. NAFLD is characterised by fat accumulation in the liver, while NASH is associated with inflammation and liver damage. Osteosarcopenia, which combines muscle and bone mass loss, is an emerging clinical problem in chronic liver disease that is often underappreciated. The reductions in muscle and bone mass share several common pathophysiological pathways; insulin resistance and chronic systemic inflammation are the most crucial predisposing factors and are related to the presence and gravity of NAFLD and to the worsening of the outcome of liver disease. This article explores the relationship between osteosarcopenia and NAFLD/MAFLD, focusing on the diagnosis, prevention and treatment of this condition in patients with CLD. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 3.0)

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Other

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8 pages, 634 KiB

Open AccessBrief Report

PNPLA3 rs738409 Genetic Variant Inversely Correlates with Platelet Count, Thereby Affecting the Performance of Noninvasive Scores of Hepatic Fibrosis

by Marica Meroni and Paola Dongiovanni

Int. J. Mol. Sci. 2023, 24(20), 15046; https://doi.org/10.3390/ijms242015046 - 10 Oct 2023

Cited by 3 | Viewed by 1597

Abstract

Noninvasive tests (NITs) including platelets (PLTs) have been proposed to replace hepatic biopsy for the diagnosis of nonalcoholic fatty liver disease (NAFLD), or as more recently redefined, metabolic dysfunction-associated steatotic liver disease (MASLD). There has been reported an inverse correlation between PLTs and [...] Read more.

Noninvasive tests (NITs) including platelets (PLTs) have been proposed to replace hepatic biopsy for the diagnosis of nonalcoholic fatty liver disease (NAFLD), or as more recently redefined, metabolic dysfunction-associated steatotic liver disease (MASLD). There has been reported an inverse correlation between PLTs and progressive MASLD, which is also affected by the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 C>G mutation. However, the correlation between low PLTs and PNPLA3 genotype has been poorly investigated. We stratified 1155 biopsy-proven MASLD patients according to PNPLA3 genotype. The hepatic expression of genes involved in megakaryopoiesis was investigated in n = 167 bariatric patients by RNAseq. PLT count progressively decreased according to the number of PNPLA3 at-risk alleles, irrespective of the presence of advanced fibrosis. The hepatic expression of genes involved in PLT biogenesis was associated with the PNPLA3 GG genotype. Finally, the presence of the PNPLA3 homozygosity flattened the accuracy of fibrosis-4 (FIB-4) in discriminating histological fibrosis stages. The PNPLA3 GG genotype may underpower the accuracy of NITs which include PLT count in identifying those patients with potentially reversible stages of fibrosis. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease/Metabolic Associated Fatty Liver Disease: New Insights 3.0)

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