Special Issue "Nutritional Intake and the Risk for Non-alcoholic Fatty Liver Disease (NAFLD)"

A special issue of Nutrients (ISSN 2072-6643).

Deadline for manuscript submissions: closed (1 September 2018).

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A printed edition of this Special Issue is available here.

Special Issue Editors

Prof. Dr. Ina Bergheim
E-Mail Website
Guest Editor
Department of Nutritional Sciences, Molecular Nutritional Science, University of Vienna, Althanstr. 14, UZA II, A-1090 Vienna, Austria
Interests: intestinal barrier; nutrition; bacterial endotoxin; alcoholic liver disease; non-alcoholic fatty liver disease; aging
Special Issues and Collections in MDPI journals
PD Dr. Jörn M. Schattenberg
E-Mail Website
Guest Editor
Department of Medicine, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
Interests: liver injury; biomarker; NASH; lifestyle intervention; NASH therapeutics; immunology; HCC

Special Issue Information

Dear Colleagues,

The aim of this Special Issue focusing on “Nutritional Intake and the Risk of Non-Alcoholic Fatty Liver Disease” is to provide an in-depth overview of the role of the intake of different macro- and micronutrients in the development and progression of non-alcoholic fatty liver disease, as well as in the prevention and treatment of this metabolic liver disease. General over-nutrition but also alterations of the dietary pattern (e.g., towards a higher intake of fat, cholesterol, and sugar—and herein especially fructose) are discussed as being critical in the development of non-alcoholic fatty liver disease (NAFLD). However, it has also been suggested that a general reduction of caloric intake and/or modulation of dietary composition, be it in regards to fat or sugar intake, may have beneficial effects on liver status in settings of NAFLD. Furthermore, in more recent years the intake of pre- and probiotics but also specific micronutrients or secondary plant compounds also discussed a means in the prevention and therapy of this disease. Despite intense research efforts during the last decades, our understanding of the interaction of nutritional intake and the development but also prevention and cure of NAFLD is still limited.

Providing a better understanding of the effects of diet and herein especially of specific macro- and micronutrients as well as pre- and probiotics and secondary plant compounds in the context of the development of NAFLD and its progression could lead to novel prevention and therapeutic strategies for this metabolic liver disease. This Special Issue will thus include original research and scientific perspectives on the relationship between NAFLD and dietary constituents that may 1) be involved in the development of the disease and 2) prevent its onset and progression. Mechanistic insights defining the contribution of certain nutritional factors (e.g., macronutrients like fat and sugar but also micronutrients and secondary plant compounds as well as pre- and probiotics) to the occurrence and management of NAFLD will improve our understanding of the disease and eventually lead to the development of universally accepted prevention and therapeutic strategies.

Prof. Dr. Ina Bergheim
PD Dr. Jörn M. Schattenberg
Guest Editors

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Keywords

  • Nutrition
  • Dietary pattern
  • Metabolism
  • Intestinal barrier and microbiota
  • Non-alcoholic fatty liver disease
  • Non-alcoholic steatohepatitis
  • Macronutrients
  • Micronutrients
  • Secondary plant compounds
  • Prebiotics
  • Probiotics

Published Papers (11 papers)

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Editorial

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Editorial
Nutritional Intake and the Risk for Non-Alcoholic Fatty Liver Disease (NAFLD)
Nutrients 2019, 11(3), 588; https://0-doi-org.brum.beds.ac.uk/10.3390/nu11030588 - 11 Mar 2019
Cited by 4 | Viewed by 1925
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising worldwide, and it is estimated that approximately one billion individuals may be afflicted with NAFLD globally [...] Full article
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Research

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Communication
Gut Permeability Might be Improved by Dietary Fiber in Individuals with Nonalcoholic Fatty Liver Disease (NAFLD) Undergoing Weight Reduction
Nutrients 2018, 10(11), 1793; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10111793 - 18 Nov 2018
Cited by 24 | Viewed by 3619
Abstract
(1) Introduction: Zonulin (ZO) has been proposed as a marker of intestinal permeability. Only a few studies have analyzed to date how diet influences the serum concentration of ZO among patients with non-alcoholic fatty liver disease (NAFLD). We performed a six-month dietetic intervention [...] Read more.
(1) Introduction: Zonulin (ZO) has been proposed as a marker of intestinal permeability. Only a few studies have analyzed to date how diet influences the serum concentration of ZO among patients with non-alcoholic fatty liver disease (NAFLD). We performed a six-month dietetic intervention to evaluate the association between fiber intake and ZO concentration in 32 individuals with NAFLD. (2) Methods: Fiber content in the diet was estimated by Food Frequency Questionnaire (FFQ) and by analyzing 72-h nutritional diaries. ZO concentrations in serum were measured before and after the intervention by immunoenzymatic assay (ELISA). Fatty liver was quantified using the Hamaguchi score before and after the dietetic intervention. (3) Results: During the intervention, the dietary fiber intake increased from 19 g/day to the 29 g/day concomitant with an increase in the frequency of fiber consumption. All patients experienced significant (all p < 0.05) improvements in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGTP) activities. We also detected decreased serum triglycerides (p = 0.036), homeostatic model assessment insulin resistance (HOMA-IR (p = 0.041) and insulin content (p = 0.34), and improvement of fatty liver status according to the Hamaguchi score (p = 0.009). ZO concentration in serum decreased by nearly 90% (7.335 ± 13.492 vs. 0.507 ± 0.762 ng/mL, p = 0.001) and correlated with the amount of dietary fiber intake (p = 0.043) as well as the degree of fatty liver (p = 0.037). (4) Conclusion: Increasing nutritional fiber results in reduced serum ZO levels, reduced liver enzymes and improved hepatic steatosis in patients with NAFLD, possibly by altering intestinal permeability. Increased dietary fiber intake should be recommended in patients with NAFLD. Full article
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Article
Non-Alcoholic Fatty Liver Disease in Overweight Children: Role of Fructose Intake and Dietary Pattern
Nutrients 2018, 10(9), 1329; https://doi.org/10.3390/nu10091329 - 19 Sep 2018
Cited by 26 | Viewed by 3567
Abstract
The role of nutrition and diet in the development of non-alcoholic fatty liver disease (NAFLD) is still not fully understood. In the present study, we determined if dietary pattern and markers of intestinal permeability differ between overweight children with and without NAFLD. In [...] Read more.
The role of nutrition and diet in the development of non-alcoholic fatty liver disease (NAFLD) is still not fully understood. In the present study, we determined if dietary pattern and markers of intestinal permeability differ between overweight children with and without NAFLD. In addition, in a feasibility study, we assessed the effect of a moderate dietary intervention only focusing on nutrients identified to differ between groups on markers of intestinal barrier function and health status. Anthropometric data, dietary intake, metabolic parameters, and markers of inflammation, as well as of intestinal permeability, were assessed in overweight children (n = 89, aged 5–9) and normal-weight healthy controls (n = 36, aged 5–9). Sixteen children suffered from early signs of NAFLD, e.g., steatosis grade 1 as determined by ultrasound. Twelve children showing early signs of NAFLD were enrolled in the intervention study (n = 6 intervention, n = 6 control). Body mass index (BMI), BMI standard deviation score (BMI-SDS), and waist circumference were significantly higher in NAFLD children than in overweight children without NAFLD. Levels of bacterial endotoxin, lipopolysaccharide-binding protein (LBP), and proinflammatory markers like interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) were also significantly higher in overweight children with NAFLD compared to those without. Total energy and carbohydrate intake were higher in NAFLD children than in those without. The higher carbohydrate intake mainly resulted from a higher total fructose and glucose intake derived from a significantly higher consumption of sugar-sweetened beverages. When counseling children with NAFLD regarding fructose intake (four times, 30–60 min within 1 year; one one-on-one counseling and three group counselings), neither alanine aminotransferase (ALT) nor aspartate aminotransferase (AST) activity in serum changed; however, diastolic blood pressure (p < 0.05) and bacterial endotoxin levels (p = 0.06) decreased markedly in the intervention group after one year. Similar changes were not found in uncounseled children. Our results suggest that a sugar-rich diet might contribute to the development of early stages of NAFLD in overweight children, and that moderate dietary counseling might improve the metabolic status of overweight children with NAFLD. Full article
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Article
Soybean Oil-Derived Poly-Unsaturated Fatty Acids Enhance Liver Damage in NAFLD Induced by Dietary Cholesterol
Nutrients 2018, 10(9), 1326; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10091326 - 18 Sep 2018
Cited by 18 | Viewed by 4316
Abstract
While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood [...] Read more.
While the impact of dietary cholesterol on the progression of atherosclerosis has probably been overestimated, increasing evidence suggests that dietary cholesterol might favor the transition from blunt steatosis to non-alcoholic steatohepatitis (NASH), especially in combination with high fat diets. It is poorly understood how cholesterol alone or in combination with other dietary lipid components contributes to the development of lipotoxicity. The current study demonstrated that liver damage caused by dietary cholesterol in mice was strongly enhanced by a high fat diet containing soybean oil-derived ω6-poly-unsaturated fatty acids (ω6-PUFA), but not by a lard-based high fat diet containing mainly saturated fatty acids. In contrast to the lard-based diet the soybean oil-based diet augmented cholesterol accumulation in hepatocytes, presumably by impairing cholesterol-eliminating pathways. The soybean oil-based diet enhanced cholesterol-induced mitochondrial damage and amplified the ensuing oxidative stress, probably by peroxidation of poly-unsaturated fatty acids. This resulted in hepatocyte death, recruitment of inflammatory cells, and fibrosis, and caused a transition from steatosis to NASH, doubling the NASH activity score. Thus, the recommendation to reduce cholesterol intake, in particular in diets rich in ω6-PUFA, although not necessary to reduce the risk of atherosclerosis, might be sensible for patients suffering from non-alcoholic fatty liver disease. Full article
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Article
Dissociation of Fatty Liver and Insulin Resistance in I148M PNPLA3 Carriers: Differences in Diacylglycerol (DAG) FA18:1 Lipid Species as a Possible Explanation
Nutrients 2018, 10(9), 1314; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10091314 - 17 Sep 2018
Cited by 22 | Viewed by 2204
Abstract
Fatty liver is tightly associated with insulin resistance and the development of type 2 diabetes. I148M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with high liver fat but normal insulin sensitivity. The underlying mechanism of the disassociation between high [...] Read more.
Fatty liver is tightly associated with insulin resistance and the development of type 2 diabetes. I148M variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is associated with high liver fat but normal insulin sensitivity. The underlying mechanism of the disassociation between high liver fat but normal insulin sensitivity remains obscure. We investigated the effect of I148M variant on hepatic lipidome of subjects with or without fatty liver, using the Lipidyzer method. Liver samples of four groups of subjects consisting of normal liver fat with wild-type PNPLA3 allele (group 1); normal liver fat with variant PNPLA3 allele (group 2); high liver fat with wild-type PNPLA3 allele (group 3); high liver fat with variant PNPLA3 allele (group 4); were analyzed. When high liver fat to normal liver fat groups were compared, wild-type carriers (group 3 vs. group 1) showed similar lipid changes compared to I148M PNPLA3 carriers (group 4 vs. group 2). On the other hand, in wild-type carriers, increased liver fat significantly elevated the proportion of specific DAGs (diacylglycerols), mostly DAG (FA18:1) which, however, remained unchanged in I148M PNPLA3 carriers. Since DAG (FA18:1) has been implicated in hepatic insulin resistance, the unaltered proportion of DAG (FA18:1) in I148M PNPLA3 carriers with fatty liver may explain the normal insulin sensitivity in these subjects. Full article
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Article
Evaluation of a High Concentrate Omega-3 for Correcting the Omega-3 Fatty Acid Nutritional Deficiency in Non-Alcoholic Fatty Liver Disease (CONDIN)
Nutrients 2018, 10(8), 1126; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10081126 - 20 Aug 2018
Cited by 16 | Viewed by 3900
Abstract
This randomized controlled trial investigated the safety and efficacy of MF4637, a high concentrate omega-3 fatty acid preparation, in correcting the omega-3 fatty acid nutritional deficiency in non-alcoholic fatty liver disease (NAFLD). The primary end point of the study was set as the [...] Read more.
This randomized controlled trial investigated the safety and efficacy of MF4637, a high concentrate omega-3 fatty acid preparation, in correcting the omega-3 fatty acid nutritional deficiency in non-alcoholic fatty liver disease (NAFLD). The primary end point of the study was set as the change of red blood cell (RBC) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by MF4637. Whether the omega-3 concentrate could lower liver fat was evaluated in a subset of patients. Furthermore, 176 subjects with NAFLD were randomized to receive the omega-3 concentrate (n = 87) or placebo (n = 89) for 24 weeks, in addition to following standard-of-care dietary guidelines. The omega-3 index, omega-6: omega-3 fatty acid ratio and quantitative measurements of RBC EPA and DHA were determined at baseline and study completion. Magnetic resonance imaging of liver fat was conducted in a subset of patients. Administration of high concentrate omega-3 for 24 weeks significantly increased the omega-3 index and absolute values of RBC EPA and DHA, and decreased the RBC omega-6: omega-3 fatty acid ratio (p < 0.0001). A significant reduction in liver fat content was reported in both groups. Full article
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Article
Circulating Phospholipid Patterns in NAFLD Patients Associated with a Combination of Metabolic Risk Factors
Nutrients 2018, 10(5), 649; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10050649 - 21 May 2018
Cited by 24 | Viewed by 3081
Abstract
Background: Non-alcoholic fatty liver disease (NAFLD) is associated with inefficient macro- and micronutrient metabolism, and alteration of circulating phospholipid compositions defines the signature of NAFLD. This current study aimed to assess the pattern of serum phospholipids in the spectrum of NAFLD, and its [...] Read more.
Background: Non-alcoholic fatty liver disease (NAFLD) is associated with inefficient macro- and micronutrient metabolism, and alteration of circulating phospholipid compositions defines the signature of NAFLD. This current study aimed to assess the pattern of serum phospholipids in the spectrum of NAFLD, and its related comorbidities and genetic modifications. Methods: 97 patients with diagnosed NAFLD were recruited at a single center during 2013–2016. Based on histological and transient elastography assessment, 69 patients were divided into non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver (NAFL) subgroups. 28 patients served as healthy controls. Serum phospholipids were determined by liquid-chromatography mass spectrometry (LC-MS/MS). Results: The total content of phosphatidylcholine (PC) and sphingomyelin in the serum was significantly increased in NAFL and NASH patients, compared to healthy controls. In addition, serum lysophospatidylethanolamine levels were significantly decreased in NAFL and NASH individuals. Circulating PC species, containing linoleic and α-linolenic acids, were markedly increased in NAFLD patients with hypertension, compared to NAFLD patients without hypertension. The pattern of phospholipids did not differ between NAFLD patients with diabetes and those without diabetes. However, NAFLD patients with hyperglycemia (blood glucose level (BGL) >100 mg/dL) exhibited significantly a higher amount of monounsaturated phosphatidylethanolamine than those with low blood glucose levels. In addition, NAFLD patients with proven GG-genotype of PNPLA3, who were at higher risk for the development of progressive disease with fibrosis, showed lower levels of circulating plasmalogens, especially 16:0, compared to those with CC- and CG-allele. Conclusions: Our extended lipidomic study presents a unique metabolic profile of circulating phospholipids associated with the presence of metabolic risk factors or the genetic background of NAFLD patients. Full article
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Article
Folate and B12 Levels Correlate with Histological Severity in NASH Patients
Nutrients 2018, 10(4), 440; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10040440 - 02 Apr 2018
Cited by 21 | Viewed by 3736
Abstract
Background: The correlation between abnormal vitamin serum levels and chronic liver disease has been previously described in literature. However, the association between the severity of folate serum levels (B9), vitamin B12 and nonalcoholic steatohepatitis (NASH) has not been widely evaluated. Therefore, the aim [...] Read more.
Background: The correlation between abnormal vitamin serum levels and chronic liver disease has been previously described in literature. However, the association between the severity of folate serum levels (B9), vitamin B12 and nonalcoholic steatohepatitis (NASH) has not been widely evaluated. Therefore, the aim of this study was to investigate the existence of such a correlation in a cohort of NASH patients. Methods: All patients aged 18 years and older who were diagnosed with biopsy-proven NASH at the EMMS hospital in Nazareth during the years 2015–2017 were enrolled in this study. Data regarding demographic, clinical and laboratory parameters was collected. Patients with other liver diseases were excluded. Results: Eighty-three NASH patients were enrolled during the study period. The mean age was 41 ± 11 years and the majority of patients were male. Mean values of folate and B12 were 9.85 ± 10.90 ng/mL and 387.53 ± 205.50 pg/mL, respectively. Half of the patients were presented with a grade 1 steatosis (43.4%), a grade 2 fibrosis (50.6%) and a grade 3 activity score (55.4%). The fibrosis grade was significantly correlated with low folate levels on multivariate analysis (p-value < 0.01). Similarly, low B12 levels were significantly associated with a higher fibrosis grade and NASH activity (p-value < 0.001 and p-value < 0.05 respectively). Conclusion: Our study demonstrated a statistically significant correlation between low levels of folate and vitamin B12 with the histological severity of NASH. These findings could have diagnostic and therapeutic implications for patient management and follow-up. Full article
Article
ChREBP Rather Than SHP Regulates Hepatic VLDL Secretion
Nutrients 2018, 10(3), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10030321 - 07 Mar 2018
Cited by 15 | Viewed by 2827
Abstract
The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small [...] Read more.
The regulation of hepatic very-low-density lipoprotein (VLDL) secretion plays an important role in the pathogenesis of dyslipidemia and fatty liver diseases. VLDL is controlled by hepatic microsomal triglyceride transfer protein (MTTP). Mttp is regulated by carbohydrate response element binding protein (ChREBP) and small heterodimer partner (SHP). However, it is unclear whether both coordinately regulate Mttp expression and VLDL secretion. Here, adenoviral overexpression of ChREBP and SHP in rat primary hepatocytes induced and suppressed Mttp mRNA, respectively. However, Mttp induction by ChREBP was much more potent than suppression by SHP. Promoter assays of Mttp and the liver type pyruvate kinase gene revealed that SHP and ChREBP did not affect the transcriptional activity of each other. Mttp mRNA and protein levels of Shp−/− mice were similar to those of wild-types; however, those of Chrebp−/−Shp−/− and Chrebp−/− mice were significantly much lower. Consistent with this, the VLDL particle number and VLDL secretion rates in Shp−/− mice were similar to wild-types but were much lower in Chrebp−/− and Chrebp−/−Shp−/− mice. These findings suggest that ChREBP, rather than SHP, regulates VLDL secretion under normal conditions and that ChREBP and SHP do not affect the transcriptional activities of each other. Full article
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Review

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Review
Muscle Loss in Chronic Liver Diseases: The Example of Nonalcoholic Liver Disease
Nutrients 2018, 10(9), 1195; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10091195 - 01 Sep 2018
Cited by 24 | Viewed by 2253
Abstract
Recent publications highlight a frequent loss of muscle mass in chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD), and its association with a poorer prognosis. In NAFLD, given the role of muscle in energy metabolism, muscle loss promotes disease progression. However, liver [...] Read more.
Recent publications highlight a frequent loss of muscle mass in chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD), and its association with a poorer prognosis. In NAFLD, given the role of muscle in energy metabolism, muscle loss promotes disease progression. However, liver damage may be directly responsible of this muscle loss. Indeed, muscle homeostasis depends on the balance between peripheral availability and action of anabolic effectors and catabolic signals. Moreover, insulin resistance of protein metabolism only partially explains muscle loss during NAFLD. Interestingly, some data indicate specific alterations in the liver–muscle axis, particularly in situations such as excess fructose/sucrose consumption, associated with increased hepatic de novo lipogenesis (DNL) and endoplasmic reticulum stress. In this context, the liver will be responsible for a decrease in the peripheral availability of anabolic factors such as hormones and amino acids, and for the production of catabolic effectors such as various hepatokines, methylglyoxal, and uric acid. A better understanding of these liver–muscle interactions could open new therapeutic opportunities for the management of NAFLD patients. Full article
Review
Beneficial and Paradoxical Roles of Anti-Oxidative Nutritional Support for Non-Alcoholic Fatty Liver Disease
Nutrients 2018, 10(8), 977; https://0-doi-org.brum.beds.ac.uk/10.3390/nu10080977 - 27 Jul 2018
Cited by 8 | Viewed by 2123
Abstract
Oxidative stress is being recognized as a key factor in the progression of chronic liver disease (CLD), especially non-alcoholic fatty liver disease (NAFLD). Many NAFLD treatment guidelines recommend the use of antioxidants, especially vitamin E. Many prospective studies have described the beneficial effects [...] Read more.
Oxidative stress is being recognized as a key factor in the progression of chronic liver disease (CLD), especially non-alcoholic fatty liver disease (NAFLD). Many NAFLD treatment guidelines recommend the use of antioxidants, especially vitamin E. Many prospective studies have described the beneficial effects of such agents for the clinical course of NAFLD. However, as these studies are usually short-term evaluations, lasting only a few years, whether or not antioxidants continue to exert favorable long-term effects, including in cases of concomitant hepatocellular carcinoma, remains unclear. Antioxidants are generally believed to be beneficial for human health and are often commercially available as health-food products. Patients with lifestyle-related diseases often use such products to try to be healthier without practicing lifestyle intervention. However, under some experimental NAFLD conditions, antioxidants have been shown to encourage the progression of hepatocellular carcinoma, as oxidative stress is toxic for cancer cells, just as for normal cells. In this review, we will highlight the paradoxical effects of antioxidants against NAFLD and related hepatocellular carcinoma. Full article
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