The Tip of the Iceberg: Non-alcoholic Fatty Liver Disease in Metabolic Disorders

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Medical Research".

Deadline for manuscript submissions: closed (29 September 2023) | Viewed by 17315

Special Issue Editors


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Guest Editor
Unit of Diabetes, Nutrition, and Metabolic Diseases, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
Interests: type 2 diabetes; obesity; insulin resistance; metabolic syndrome; cardiovascular risk in metabolic diseases
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. Department M3, Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, 540142 Târgu Mureş, Romania
2. Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, 540136 Târgu Mureş, Romania
Interests: diabetes mellitus; beta cell; MASLD; fat; leptin
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metabolic disorders, such as type 2 diabetes mellitus, obesity, dyslipidaemias, and metabolic syndrome, have expanded at an alarming speed during recent decades and today account for hundreds of millions of cases worldwide. Their severe impact on public health systems is triggered by the large number of chronic complications they generate. Recent decades have brought new understanding to this issue, and researchers have identified complementary pathogenic pathways to link metabolic disorders to various clinical manifestations, which can thus be regarded as additional organ expressions of the same category of health problems. One of the clinical entities that has become strongly connected with metabolic disorders is non-alcoholic fatty liver disease (NAFLD), which is today considered the hepatic consequence of systemic insulin resistance and the liver’s expression of metabolic syndrome. NAFLD expansion has closely followed the rapidly increasing number of patients with obesity, type 2 diabetes, and dyslipidaemias, and has become the most frequent liver disease worldwide today. This hepatic disorder leads to an increased risk for both advanced liver disease and cardiovascular disease, thus limiting life expectancy and quality in a large number of patients. The close correlation NAFLD has with metabolic disorders is highlighted by the recent move to rename it metabolic dysfunction-associated fatty liver disease (MAFLD). This Special Issue focuses precisely on this close relationship and aims to depict it from a broader perspective, starting with the exploration of NAFLD-inducing pathogenic mechanisms that develop around insulin resistance, and going all the way to clinical considerations that centre on this connection.

Dr. Cristina Mihaela Lacatusu
Dr. Simona Cernea
Guest Editors

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Keywords

  • non-alcoholic fatty liver disease (NAFLD)
  • metabolic dysfunction-associated fatty liver disease (MAFLD)
  • insulin resistance
  • metabolic syndrome
  • type 2 diabetes
  • obesity
  • dyslipidaemias

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Published Papers (6 papers)

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Research

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19 pages, 4738 KiB  
Article
The Development of Nonalcoholic Fatty Liver Disease and Metabolic Syndromes in Diet-Induced Rodent Models
by Bayan Abdulhafid Aljahdali, Adnan Salem Bajaber, Doha M. Al-Nouri, Abdulrahman Saleh Al-Khalifah, Shaista Arzoo and Abeer Abdullah Alasmari
Life 2023, 13(6), 1336; https://doi.org/10.3390/life13061336 - 7 Jun 2023
Cited by 1 | Viewed by 2281
Abstract
Dietary macronutrients are essential for metabolic regulation and insulin function. The present study examined the effects of different high-fat diets (HFDs) and high-carbohydrate diets (HCDs) on the development of non-alcoholic fatty liver disease and metabolic syndrome indices in healthy adult male Wistar albino [...] Read more.
Dietary macronutrients are essential for metabolic regulation and insulin function. The present study examined the effects of different high-fat diets (HFDs) and high-carbohydrate diets (HCDs) on the development of non-alcoholic fatty liver disease and metabolic syndrome indices in healthy adult male Wistar albino rats. Forty-two rats were distributed into six groups (n = 7), which were fed the following for 22 weeks: (1) a control diet; (2) a high-carbohydrate, low-fat diet (HCD-LFD); (3) high-saturated-fat, low-carbohydrate diet (HSF-LCD); (4) a high-monounsaturated-fat diet (HMUSF); (5) a high medium-chain fat diet (HMCF); and a (6) a high-carbohydrate, high-fiber diet (HCHF). In comparison to the control, the body weight increased in all the groups. The HSF-LCD group showed the highest levels of cholesterol, triglyceride, low-density lipoprotein, hepatic enzyme, insulin resistance, and Homeostatic Model Assessment for Insulin Resistance. A liver histology analysis of the HSF-LCD group showed macrovesicular hepatic steatosis associated with large hepatic vacuolation. Additionally, it showed marked periportal fibrosis, especially around the blood vessels and blood capillaries. The lowest levels of fasting glycemia, insulin, and HOMA-IR were observed in the HCHF group. In conclusion, these findings show that dietary saturated fat and cholesterol are principal components in the development and progression of non-alcoholic fatty liver disease in rats, while fiber showed the greatest improvement in glycemic control. Full article
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12 pages, 291 KiB  
Article
Low–Normal Thyroid Function Is Not Associated with Either Non-Alcoholic Fatty Liver Disease or with Metabolic Dysfunction-Associated Fatty Liver Disease
by Julia Zuarth-Vázquez, Lidia Moreno-Castañeda, Juan Pablo Soriano-Márquez, Alain Velázquez-Alemán, Martha Helena Ramos-Ostos, Misael Uribe, Iván López-Méndez and Eva Juárez-Hernández
Life 2023, 13(4), 1048; https://doi.org/10.3390/life13041048 - 19 Apr 2023
Cited by 1 | Viewed by 1659
Abstract
Background: The association of low–normal thyroid function (LNTF) with non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) is controversial; thus, the aim of this study is to determine this association. Methods: NAFLD was evaluated by controlled attenuation parameter of [...] Read more.
Background: The association of low–normal thyroid function (LNTF) with non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated fatty liver disease (MAFLD) is controversial; thus, the aim of this study is to determine this association. Methods: NAFLD was evaluated by controlled attenuation parameter of transient elastography. Patients were classified by MAFLD criteria. LNTF was defined as TSH levels of 2.5 to 4.5 mIU/L and were divided into three different cut-off points (>4.5 to 5.0, >3.1, and >2.5 mIU/L). Associations between LNTF, NAFLD, and MAFLD were evaluated by univariate and multivariate logistic regression analyses. Results: A total of 3697 patients were included; 59% (n = 2179) were male, and median age and body mass index were 48 (43–55) years and 25.9 (23.6–28.5) kg/m2, respectively, and 44% (n = 1632) were diagnosed with NAFLD. THS levels of 2.5 and 3.1 showed significant associations with the presence of NAFLD and MAFLD; however, LNTF did not show an independent association with the presence of NAFLD or MAFLD in multivariate analysis. According to different cut-off points, patients with LNTF presented similar risks for NAFLD as the general population. Conclusion: LNTF is not associated with NAFLD or MAFLD. Patients with high LNTF are equally at risk for NAFLD as the general population. Full article

Review

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23 pages, 837 KiB  
Review
NAFLD Fibrosis Progression and Type 2 Diabetes: The Hepatic–Metabolic Interplay
by Simona Cernea
Life 2024, 14(2), 272; https://doi.org/10.3390/life14020272 - 18 Feb 2024
Cited by 3 | Viewed by 2618
Abstract
The bidirectional relationship between type 2 diabetes and (non-alcoholic fatty liver disease) NAFLD is indicated by the higher prevalence and worse disease course of one condition in the presence of the other, but also by apparent beneficial effects observed in one, when the [...] Read more.
The bidirectional relationship between type 2 diabetes and (non-alcoholic fatty liver disease) NAFLD is indicated by the higher prevalence and worse disease course of one condition in the presence of the other, but also by apparent beneficial effects observed in one, when the other is improved. This is partly explained by their belonging to a multisystemic disease that includes components of the metabolic syndrome and shared pathogenetic mechanisms. Throughout the progression of NAFLD to more advanced stages, complex systemic and local metabolic derangements are involved. During fibrogenesis, a significant metabolic reprogramming occurs in the hepatic stellate cells, hepatocytes, and immune cells, engaging carbohydrate and lipid pathways to support the high-energy-requiring processes. The natural history of NAFLD evolves in a variable and dynamic manner, probably due to the interaction of a variable number of modifiable (diet, physical exercise, microbiota composition, etc.) and non-modifiable (genetics, age, ethnicity, etc.) risk factors that may intervene concomitantly, or subsequently/intermittently in time. This may influence the risk (and rate) of fibrosis progression/regression. The recognition and control of the factors that determine a rapid progression of fibrosis (or its regression) are critical, as the fibrosis stages are associated with the risk of liver-related and all-cause mortality. Full article
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24 pages, 433 KiB  
Review
Non-Invasive Diagnostic of NAFLD in Type 2 Diabetes Mellitus and Risk Stratification: Strengths and Limitations
by Alina Boeriu, Daniela Dobru and Crina Fofiu
Life 2023, 13(12), 2262; https://doi.org/10.3390/life13122262 - 27 Nov 2023
Cited by 3 | Viewed by 1865
Abstract
The progressive potential of liver damage in type 2 diabetes mellitus (T2DM) towards advanced fibrosis, end-stage liver disease, and hepatocarcinoma has led to increased concern for quantifying liver injury and individual risk assessment. The combination of blood-based markers and imaging techniques is recommended [...] Read more.
The progressive potential of liver damage in type 2 diabetes mellitus (T2DM) towards advanced fibrosis, end-stage liver disease, and hepatocarcinoma has led to increased concern for quantifying liver injury and individual risk assessment. The combination of blood-based markers and imaging techniques is recommended for the initial evaluation in NAFLD and for regular monitoring to evaluate disease progression. Continued development of ultrasonographic and magnetic resonance imaging methods for accurate quantification of liver steatosis and fibrosis, as well as promising tools for the detection of high-risk NASH, have been noted. In this review, we aim to summarize available evidence regarding the usefulness of non-invasive methods for the assessment of NAFLD in T2DM. We focus on the power and limitations of various methods for diagnosis, risk stratification, and patient monitoring that support their implementation in clinical setting or in research field. Full article
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13 pages, 595 KiB  
Review
Challenges and Solutions in the Management of Hepatocellular Carcinoma Associated with Non-Alcoholic Fatty Liver Disease
by Ramona Cadar, Corina Lupascu Ursulescu, Alin Mihai Vasilescu, Ana Maria Trofin, Mihai Zabara, Delia Rusu-Andriesi, Bogdan Ciuntu, Cristina Muzica and Cristian Dumitru Lupascu
Life 2023, 13(10), 1987; https://doi.org/10.3390/life13101987 - 29 Sep 2023
Cited by 5 | Viewed by 1946
Abstract
Non-alcoholic fatty liver disease (NAFLD) has gained attention in the last few years due to its increasing prevalence worldwide becoming a global epidemic. The increasing incidence of NAFLD and the concurrent increase in the number of hepatocellular carcinoma (HCC) cases at a global [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) has gained attention in the last few years due to its increasing prevalence worldwide becoming a global epidemic. The increasing incidence of NAFLD and the concurrent increase in the number of hepatocellular carcinoma (HCC) cases at a global level is a matter of concern. HCC has several risk factors, of which NAFLD and its associated metabolic disturbances—type 2 diabetes mellitus, obesity, and dyslipidemia—are of great interest due to their accelerating rise in incidence worldwide. There is a high amount of data derived from basic and clinical studies that reveal the molecular pathways that drive NAFLD-associated HCC. Based on these findings, new prevention, surveillance, and treatment strategies are emerging. However, current data on treatment modalities in NAFLD-associated HCC are still scarce, though the results from non-NAFLD HCC studies are promising and could provide a basis for a future research agenda to address NAFLD/NASH patients. Clinicians should carefully assess all the clinical and radiological parameters and establish a prognosis based on the Barcelona Clinic Liver Cancer classification and discuss in a multidisciplinary team the treatment strategy. The specific factors associated with NAFLD-associated HCC which can have a negative impact on survival even in patients with early HCC, such as cardiovascular disease, type 2 diabetes, and obesity, should be taken into consideration. This review aims to discuss the latest recommendations regarding the diagnosis and treatment of NAFLD-associated HCC and the remaining challenges. Full article
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17 pages, 513 KiB  
Review
Pathogenesis of Alcoholic Fatty Liver a Narrative Review
by Helmut K. Seitz, Bernardo Moreira and Manuela G. Neuman
Life 2023, 13(8), 1662; https://doi.org/10.3390/life13081662 - 30 Jul 2023
Cited by 8 | Viewed by 6273
Abstract
Alcohol effect hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as dietary fat (saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)) may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate [...] Read more.
Alcohol effect hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as dietary fat (saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)) may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferator activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c). The inhibition of AMPK, and thus of PPARα, results in an inhibition of FA oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1)-driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons. On the other side, the secretion of FAs via very-low-density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor α (TNF α), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver. Alcohol-induced gut dysbiosis contributes to the severity of ALD by increasing the metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen-associated molecular patterns (PAMPS) via specific Toll-like receptor (TLR) bacterial overgrowth leads to the translocation of bacteria. Endotoxins and toxic ethanol metabolites enter the enterohepatic circulation, reaching the liver and inducing the activation of the nuclear factor kappa-B (NFκB) pathway. Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in favour of necrosis. Full article
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