Development Of Metabolic Diseases Research Articles

The Effects of Antioxidant Supplementation on the Pathologic Mechanisms of Metabolic Syndrome and Cardiovascular Disease Development

The Effects of Antioxidant Supplementation on the Pathologic Mechanisms of Metabolic Syndrome and Cardiovascular Disease Development

Genetic predisposition to metabolic dysfunction-associated fatty liver disease

The literature review highlights the issue of genetic risk factors associated with the development of metabolic dysfunction-associated fatty liver disease. Human genetic examinations revealed 132 genes among which 32 loci are strongly associated with the pathogenesis of metabolic dysfunction-associated fatty liver disease. It has been found that the risk of developing metabolic dysfunction-associated fatty liver disease is carried by single-nucleotide variants of various genes whose products are involved in lipid and carbohydrate metabolism, maintenance of the redox state, the development of inflammation and fibrosis of liver tissue, which are components of metabolic dysfunction-associated fatty liver disease reactome. The authors presented a detailed list of genetic factors singling out those that influence the risk of metabolic dysfunction-associated fatty liver disease and directly metabolic dysfunction-associated steatohepatitis and liver fibrosis. Also, they emphasized that it is the single-nucleotide variants of the genes of protein 3 containing a patatin-like phospholipase domain, transmembrane 6 superfamily member 2, and 17b-hydroxysteroid dehydrogenase type 13 that are characte­rized by the highest degree of association with metabolic dysfunction-associated fatty liver disease (odds ratio > 1.6) compared to single-nucleotide variants of other genes identified by gene association studies. The combination of several polymorphisms increases the risk of development and severity of metabolic dysfunction-associated fatty liver disease. The additive steatogenic effect of protein 3 single-nucleotide gene variants containing a patatin-like phospholipase domain and transmembrane 6 superfamily member 2 is probably due to an increased expression of genes involved in de novo lipogenesis. The authors emphasize the need for genetic risk assessment of metabolic dysfunction-associated fatty liver disease, which should include molecular genetic testing at an early stage of examination.

The use of an in vitro fecal fermentation model to uncover the beneficial role of omega-3 and punicic acid in gut microbiota alterations induced by a Western diet.

The influence of gut microbiota in the onset and development of several metabolic diseases has gained attention over the last few years. Diet plays an essential role in gut microbiota modulation. Western diet (WD), characterized by high-sugar and high-fat consumption, alters gut microbiome composition, diversity index, microbial relative levels, and functional pathways. Despite the promising health effects demonstrated by polyunsaturated fatty acids, their impact on gut microbiota is still overlooked. The effect of Fish oil (omega-3 source) and Pomegranate oil (punicic acid source), and a mixture of both oils in gut microbiota modulation were determined by subjecting the oil samples to in vitro fecal fermentations. Cecal samples from rats from two different dietary groups: a control diet (CD) and a high-fat high-sugar diet (WD), were used as fecal inoculum. 16S amplicon metagenomics sequencing showed that Fish oil + Pomegranate oil from the WD group increased α-diversity. This sample can also increase the relative abundance of the Firmicutes and Bacteroidetes phylum as well as Akkermansia and Blautia, which were affected by the WD consumption. All samples were able to increase butyrate and acetate concentration in the WD group. Moreover, tyrosine concentrations, a precursor for dopamine and norepinephrine, increase in the Fish oil + Pomegranate oil WD sample. GABA, an important neurotransmitter, was also increased in WD samples. These results suggest a potential positive impact of these oils' mixture on gut-brain axis modulation. It was demonstrated, for the first time, the great potential of using a mixture of both Fish and Pomegranate oil to restore the gut microbiota changes associated with WD consumption.

Epigenetics of the non-coding RNA nc886 across blood, adipose tissue and skeletal muscle in offspring exposed to diabetes in pregnancy

BackgroundDiabetes in pregnancy is associated with increased risk of long-term metabolic disease in the offspring, potentially mediated by in utero epigenetic variation. Previously, we identified multiple differentially methylated single CpG sites in offspring of women with gestational diabetes mellitus (GDM), but whether stretches of differentially methylated regions (DMRs) can also be identified in adolescent GDM offspring is unknown. Here, we investigate which DNA regions in adolescent offspring are differentially methylated in blood by exposure to diabetes in pregnancy. The secondary aim was to characterize the RNA expression of the identified DMR, which contained the nc886 non-coding RNA.MethodsTo identify DMRs, we employed the bump hunter method in samples from young (9–16 yr, n = 92) offspring of women with GDM (O-GDM) and control offspring (n = 94). Validation by pyrosequencing was performed in an adult offspring cohort (age 28–33 years) consisting of O-GDM (n = 82), offspring exposed to maternal type 1 diabetes (O-T1D, n = 67) and control offspring (O-BP, n = 57). RNA-expression was measured using RT-qPCR in subcutaneous adipose tissue and skeletal muscle.ResultsOne significant DMR represented by 10 CpGs with a bimodal methylation pattern was identified, located in the nc886/VTRNA2-1 non-coding RNA gene. Low methylation status across all CpGs of the nc886 in the young offspring was associated with maternal GDM. While low methylation degree in adult offspring in blood, adipose tissue, and skeletal muscle was not associated with maternal GDM, adipose tissue nc886 expression was increased in O-GDM compared to O-BP, but not in O-T1D. In addition, adipose tissue nc886 expression levels were positively associated with maternal pre-pregnancy BMI (p = 0.006), but not with the offspring’s own adiposity.ConclusionsOur results highlight that nc886 is a metastable epiallele, whose methylation in young offspring is negatively correlated with maternal obesity and GDM status. The physiological effect of nc886 may be more important in adipose tissue than in skeletal muscle. Further research should aim to investigate how nc886 regulation in adipose tissue by exposure to GDM may contribute to development of metabolic disease.

Regulation of placental amino acid transport in health and disease.

Abnormal fetal growth, i.e., intrauterine growth restriction (IUGR) or fetal growth restriction (FGR) and fetal overgrowth, is associated with increased perinatal morbidity and mortality and is strongly linked to the development of metabolic and cardiovascular disease in childhood and later in life. Emerging evidence suggests that changes in placental amino acid transport may contribute to abnormal fetal growth. This review is focused on amino acid transport in the human placenta, however, relevant animal models will be discussed to add mechanistic insights. At least 25 distinct amino acid transporters with different characteristics and substrate preferences have been identified in the human placenta. Of these, System A, transporting neutral nonessential amino acids, and System L, mediating the transport of essential amino acids, have been studied in some detail. Importantly, decreased placental Systems A and L transporter activity is strongly associated with IUGR and increased placental activity of these two amino acid transporters has been linked to fetal overgrowth in human pregnancy. An array of factors in the maternal circulation, including insulin, IGF-1, and adiponectin, and placental signaling pathways such as mTOR, have been identified as key regulators of placental Systems A and L. Studies using trophoblast-specific gene targeting in mice have provided compelling evidence that changes in placental Systems A and L are mechanistically linked to altered fetal growth. It is possible that targeting specific placental amino acid transporters or their upstream regulators represents a novel intervention to alleviate the short- and long-term consequences of abnormal fetal growth in the future.

Hepatic steatosis induced by nicotine plus Coca-Cola™ is prevented by nicotinamide riboside (NR).

Cigarettes containing nicotine (Nic) are a risk factor for the development of cardiovascular and metabolic diseases. We reported that Nic delivered via injections or e-cigarette vapor led to hepatic steatosis in mice fed with a high-fat diet. High-fructose corn syrup (HFCS) is the main sweetener in sugar-sweetened beverages (SSBs) in the US. Increased consumption of SSBs with HFCS is associated with increased risks of non-alcoholic fatty liver disease (NAFLD). Nicotinamide riboside (NR) increases mitochondrial nicotinamide adenine dinucleotide (NAD+) and protects mice against hepatic steatosis. This study evaluated if Nic plus Coca-Cola™ (Coke) with HFCS can cause hepatic steatosis and that can be protected by NR. C57BL/6J mice received twice daily intraperitoneal (IP) injections of Nic or saline and were given Coke (HFCS), or Coke with sugar, and NR supplementation for 10 weeks. Our results show that Nic+Coke caused increased caloric intake and induced hepatic steatosis, and the addition of NR prevented these changes. Western blot analysis showed lipogenesis markers were activated (increased cleavage of the sterol regulatory element-binding protein 1 [SREBP1c] and reduction of phospho-Acetyl-CoA Carboxylase [p-ACC]) in the Nic+Coke compared to the Sal+Water group. The hepatic detrimental effects of Nic+Coke were mediated by decreased NAD+ signaling, increased oxidative stress, and mitochondrial damage. NR reduced oxidative stress and prevented mitochondrial damage by restoring protein levels of Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1) signaling. We conclude that Nic+Coke has an additive effect on producing hepatic steatosis, and NR is protective. This study suggests concern for the development of NAFLD in subjects who consume nicotine and drink SSBs with HFCS.

Abstract PO3-13-08: D17104: Aryl Hydrocarbon Receptor Signaling and Other Biomarkers of Fat Metabolism in Human Mammary Adipose Tissue from Women with Malignant Breast Disease

Abstract Background: Obesity is a recognized risk factor for the development of metabolic disease and breast cancer possibly due to chronic inflammation mediated by cytokines secreted by adipose tissue. Given this, our group examined differential expression of several markers of chronic inflammation in adipose tissue of both benign and malignant breast tissue from patients. The aryl hydrocarbon receptor (AhR) is an important cytosolic, ligand-dependent transcription factor found within hepatocytes and adipocytes that is upregulated in many types of cancer. AhR promotes the initiation, progression, and metastasis of cancer cells allowing certain cancers to evade immune recognition (Xue et al. Front. Immunology 2018). Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that generates kynurenine (KYN) from tryptophan (TRP), which acts as an AhR agonist. We sought to determine expression of IDO1 via immunohistochemistry (IHC) in mammary adipose tissue associated with benign or malignant breast. We hypothesized that adipose tissue adjacent to malignant breast tissue may have heightened expression of IDO1 in addition to Cyp1b1, and SPP1; both of which are also markers of increased aryl-hydrocarbon transcriptional activity, compared to adipose tissue noncontiguous to malignant lesions. KYN affects gene expression for insulin resistance and levels are elevated in plasma of older obese women compared to lean women; however, the relationship to breast malignancy is not known. Methods: IDO1 (Cell Signaling, 1:200), Cyp1b1 (Thermo Fisher, 1:300), and SPP1 (Thermo Fisher, 1:200) IHC was performed according to the manufacturers' protocols. Adipose tissue immediately adjacent to, and >2 mm away from, tumors (three DCIS, 11 invasive carcinomas) was evaluated in 14 patients. Adipose tissue in separate tissue blocks from benign breast tissue (three ipsilateral, 11 contralateral) in the same patients was also evaluated. Human plasma KYN levels were assayed by HPLC in the Dartmouth Clinical Pharmacology Shared Resource as described previously (Rojas et al. Obesity 2021). Results: In this preliminary pilot study, there was no difference in staining pattern for IDO1 in adipose tissue present in malignant and benign samples. Two patients showed increased Cyp1b1 and SPP1 staining immediately adjacent to the invasive carcinoma (Figure 1). Patients with benign breast disease did not show increased Cyp1b1 or SPP1 staining. Results will be confirmed using qPCR for mRNA. Plasma samples from patients with benign disease showed a lower level of KYN expression on average (0.370 ug/mL, N = 8) compared to plasma from patients with malignant disease (0.424, N = 10). Additionally, the ratio of KYN:TRP was lower in the benign group (0.065) compared to the cohort with malignancy (0.080). Univariate linear regression will be used to further assess relationships between continuous variables in the study population (e.g., patient age, BMI, KYN plasma levels, benign vs malignant breast disease). Regression lines and the associated slope estimates (b-value) and p-values for regression models will be provided on scatter plots. Conclusions: While there was no difference in IDO1 staining patterns in adipose tissue of malignant and benign samples in this group, tissue samples from patients with invasive carcinoma demonstrated increased Cyp1b1 and SPP1 staining adjacent to the malignant tumor; while benign tissue samples did not show a positive stain. This suggests increased aryl-hydrocarbon transcriptional activity in invasive breast carcinoma—further linking AhR signaling with adipose tissue immune dysregulation and invasive malignancy. Additionally, KYN plasma levels were higher in patients with malignant disease indicating a possible relationship between insulin resistance and breast malignancy. Additional research may offer new insights relating to this important pathway and ultimately treatments aimed at blunting its nefarious effects. Citation Format: Adam Ephraim, Jonathan Pirruccello, Scott Palisoul, Jonathan Marotti, Mary Chamberlin. D17104: Aryl Hydrocarbon Receptor Signaling and Other Biomarkers of Fat Metabolism in Human Mammary Adipose Tissue from Women with Malignant Breast Disease [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-08.

The Integrated Stress Response Regulates Diurnal Rhythms in Liver Metabolism

Disruptions in biological rhythms are associated with the development of metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insuffciency and activator of the integrated stress response (ISR), plays an integral role in liver metabolism. The objective of this work was to examine the impact of feeding a low protein quality (LPQ) diet on diurnal rhythms in liver metabolism. We hypothesized that activation of the ISR by GCN2 maintains metabolic rhythms within the liver during LPQ feeding. To address our objective, wild type (WT) and whole body Gcn2 knockout (GCN2KO) mice were housed in total darkness and provided free access to either a Control or a LPQ diet (devoid of leucine) for 8-days and then killed at 2 circadian time (CT) points 12-hours apart (CT3, CT15). WT mice fed a Control diet showed oscillations in hepatic ISR activation that were lost in the livers of GCN2KO mice. Diurnal patterns in the liver transcriptome including genes regulating triglyceride metabolism were also dampened in GCN2KO mice. WT mice fed LPQ showed increased hepatic ISR activation and greater abundance of ISR target genes relative to Control only at CT15 (p<0.05 by two factor ANOVA). GCN2KO mice fed LPQ failed to show oscillations in ISR activation and instead displayed reductions in liver intracellular amino acids alongside significant upregulation of genes encoding gluconeogenesis and amino acid catabolism at CT15 (q<0.05, Log2FC>1). In conclusion, GCN2 is required for diurnal ISR activation and execution in the liver. LPQ feeding increases hepatic ISR activation in a time dependent manner. Sensing of LPQ by GCN2 is necessary for the maintenance of rhythms in liver macronutrient metabolism. NIH DK109714, Pilot award from the NJ IFNH Center for Human Nutrition, Exercise, and Metabolism (NExT). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Multi-Functional Role of RECK in Metabolic Dysfunction-Associated Steatotic Liver Disease Development: A Mass Spectrometry-Proteomic Approach

Metabolic dysfunction-associated steatotic liver disease (MASLD, previously referred to as nonalcoholic fatty liver disease) is characterized by increased fat deposition and inflammation in the liver as well as dysregulation of cellular processes that affect the extracellular matrix (ECM). We previously observed that the expression of Reversion Inducing Cysteine Rich Protein with Kazal motifs (RECK), a key ECM regulatory protein, negatively correlates with MASLD-associated fibrosis and inflammation (metabolic dysfunction-associated steatohepatitis, MASH). However, mechanisms governing this relationship remain unclear. Therefore, we hypothesized that overexpression of RECK is hepatoprotective in the setting of MASH by altering several ECM-linked pathways, as analyzed by proteomics. Accordingly, we generated hepatocyte-specific Reck-overexpressing transgenic mice. Male hepatocyte-specific Reck-overexpressing transgenic mice and littermate controls were fed a Western diet high in fat, carbohydrate, and cholesterol for 24 weeks (n=6/group). Whole liver tissue was submitted for mass spectrometry-proteomic analysis. We identified 370 differentially expressed proteins out of a total of 4693 proteins using a q-value cutoff of ≤0.10; of which 90 proteins were significantly upregulated while 280 significantly downregulated. This included an upregulation of Cyp2b (adjusted p≤0.01) and downregulation of Taok1, C/EBPβ, and Vitronectin (all adjusted p≤0.01), all of which have been shown to be important in liver health and metabolism in the context of MASH. Predictive pathway analysis using Ingenuity Pathway Analysis software (Qiagen) identified several significantly altered pathways, including those involved in ECM regulator pathways (integrin signaling, z-score=6.0; mTOR signaling, z-score=5.3; leukocyte extravasation signaling, z-score=5.1), cell-signaling (chemokine signaling, z-score=5.4; CXCR4 signaling chemokine signaling, z-score=5.0), and inflammatory responses (leukocyte extravasation signaling, z-score=5.1; CXCR4 signaling, z-score=5.0). Interestingly, pathway analysis based on significantly altered proteins predicted the downregulation of critical components of hepatic inflammation and fibrosis, including TGF-β, IL-1β, and TNFα. These novel results reveal the regulatory role of RECK in MASH progression, specifically governing the components of ECM remodeling and inflammation. Our goal is to develop RECK inducers and identify additional therapeutic targets in MASH development and progression. This work was funded by the NIH award R01DK130243. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hepatic lipid droplet-associated proteome changes distinguish dietary-induced fatty liver from glucose tolerance in male mice.

Fatty liver is characterized by the expansion of lipid droplets (LDs) and is associated with the development of many metabolic diseases. We assessed the morphology of hepatic LDs and performed quantitative proteomics in lean, glucose-tolerant mice compared to high-fat diet (HFD) fed mice that displayed hepatic steatosis and glucose intolerance as well as high-starch diet (HStD) fed mice who exhibited similar levels of hepatic steatosis but remained glucose tolerant. Both HFD and HStD-fed mice had more and larger LDs than Chow-fed animals. We observed striking differences in liver LD proteomes of HFD and HStD-fed mice compared to Chow-fed mice, with fewer differences between HFD and HStD. Taking advantage of our diet strategy, we identified a fatty liver LD proteome consisting of proteins common in HFD- and HStD-fed mice, as well as a proteome associated with glucose tolerance that included proteins shared in Chow and HStD but not HFD-fed mice. Notably, glucose intolerance was associated with changes in the ratio of adipose triglyceride lipase to perilipin 5 in the LD proteome, suggesting dysregulation of neutral lipid homeostasis in glucose-intolerant fatty liver. We conclude that our novel dietary approach uncouples ectopic lipid burden from insulin resistance-associated changes in the hepatic lipid droplet proteome.

Impact of alcohol consumption on metabolic dysfunction-associated fatty liver disease development and remission: A longitudinal cohort study.

The influence of alcohol intake on metabolic dysfunction-associated fatty liver disease (MAFLD) development and remission remains unclear; thus, we aimed to investigate their longitudinal associations. This observational cohort study included 6349 patients who underwent more than two health check-ups over >2 years between April 2013 and March 2021. Generalized estimation equations were used to analyse the longitudinal associations between changes in alcohol intake and MAFLD according to repeated measures at baseline and the most recent stage. The MAFLD development and remission rates were 20.4 and 5.1 and 9.1 and 4.7% in men and women, respectively. Although alcohol consumption was not a significant factor for MAFLD development, consuming 0.1-69.9 g/week (odds ratio [OR]: 0.672, 95% confidence interval [CI]: 0.469-0.964, p < .05) and ≥280 g/week were significant factors for MAFLD development in males (OR: 1.796, 95% CI: 1.009-3.196, p < .05) and females (OR: 16.74, 95% CI: 3.877-72.24, p < .001). Regardless of quantity and frequency, alcohol consumption was not a significant factor for MAFLD remission. Several noninvasive liver fibrosis scores were significantly associated with alcohol intake quantity and frequency in males with MAFLD development and remission (p < .05). The nonalcoholic fatty liver disease fibrosis score differed significantly between males with and without reduced alcohol intake (p < .05) who showed MAFLD remission. Although the influence of alcohol intake on MAFLD development and remission differed, alcohol consumption was not beneficial for MAFLD remission in either sex. Alcohol intake reduction or cessation is recommended to prevent liver fibrosis, even in those who achieve MAFLD remission.

Bazi Bushen ameliorates age-related energy metabolism dysregulation by targeting the IL-17/TNF inflammatory pathway associated with SASP

BackgroundChronic inflammation and metabolic dysfunction are key features of systemic aging, closely associated with the development and progression of age-related metabolic diseases. Bazi Bushen (BZBS), a traditional Chinese medicine used to alleviate frailty, delays biological aging by modulating DNA methylation levels. However, the precise mechanism of its anti-aging effect remains unclear. In this study, we developed the Energy Expenditure Aging Index (EEAI) to estimate biological age. By integrating the EEAI with transcriptome analysis, we aimed to explore the impact of BZBS on age-related metabolic dysregulation and inflammation in naturally aging mice.MethodsWe conducted indirect calorimetry analysis on five groups of mice with different ages and utilized the data to construct EEAI. 12 -month-old C57BL/6 J mice were treated with BZBS or β-Nicotinamide Mononucleotide (NMN) for 8 months. Micro-CT, Oil Red O staining, indirect calorimetry, RNA sequencing, bioinformatics analysis, and qRT-PCR were performed to investigate the regulatory effects of BZBS on energy metabolism, glycolipid metabolism, and inflammaging.ResultsThe results revealed that BZBS treatment effectively reversed the age-related decline in energy expenditure and enhanced overall metabolism, as indicated by the aging index of energy expenditure derived from energy metabolism parameters across various ages. Subsequent investigations showed that BZBS reduced age-induced visceral fat accumulation and hepatic lipid droplet aggregation. Transcriptomic analysis of perirenal fat and liver indicated that BZBS effectively enhanced lipid metabolism pathways, such as the PPAR signaling pathway, fatty acid oxidation, and cholesterol metabolism, and improved glycolysis and mitochondrial respiration. Additionally, there was a significant improvement in inhibiting the inflammation-related arachidonic acid-linoleic acid metabolism pathway and restraining the IL-17 and TNF inflammatory pathways activated via senescence associated secretory phenotype (SASP).ConclusionsBZBS has the potential to alleviate inflammation in metabolic organs of naturally aged mice and maintain metabolic homeostasis. This study presents novel clinical therapeutic approaches for the prevention and treatment of age-related metabolic diseases.

Up Date from the Factors Related to the Development of Endocrine Diseases: A perspective biological chemistry

The endocrine system contributes to the functioning of the body's metabolism, the increase or decrease in hormones favors the formation of disorders that develop metabolic diseases. Aim. Compile information on factors that intervene in the development of endocrinological diseases, mainly in hormonal action and alterations of certain metabolites. Methodology. A bib¬liographic search was carried out in Google Schoolar and PudMed using keywords, the information was analyzed in pairs. Results. Hormonal action is affected by desynchronization in hormonal production, triggering metabolic diseases. Measurement of calcium, phosphorus, PTH, 25OHD, 1.25OHD, calcitonin and osteocalcin help in the diagnosis. Conclusion. Circadian alterations favor the development of metabolic diseases, the participation of the clinical laboratory with specific tests is important.

От неалкогольной к метаболически ассоциированной жировой болезни печени. Стеатометрия и кардиометаболические факторы как предикторы развития стеатогепатита

Non-alcoholic metabolic dysfunction-associated fatty liver disease is the most common liver sickness linked with the high risk of hepatic and extrahepatic complications. The article provides an overview of changes in the nomenclature of this disease, analysis of risk factors for its development and the results of own research. The aim of the study was to estimate the clinical significance of steatometry (CAP function) by Fibroscan and cardiometabolic factors in assessing the risk of steatohepatitis development. Material and methods. Patients with hepatic steatosis accompanied by metabolic disorders were examined. Steatometry as well as routine physical and laboratory examination, including biochemical blood tests and abdominal ultrasound were provided. Statistical analysis included χ2 test, Spearman's rank correlation test, Student's t-test, Mann–Whitney test, multiple linear regression analysis. Results. 74 patients were included. Main characteristics of the cohort: 62.2% male, mean age – 48.8 years, cases of steatohepatitis – 41.9%. It was revealed that the number of metabolic factors in an individual patient correlated with the presence of steatohepatitis (χ2 = 3.29; p &lt; 0.05) and the severity of steatosis by steatometry (rs = 0.37; p &lt; 0.05). Individual clinical and laboratory parameters influenced the severity of steatosis with varying degrees. The most significant parameters were: abdominal circumference, concentration of HDL, insulin, activity of ALT, GGTP, and the presence of arterial hypertension. Using these indicators, a formula for assessing the risk of severe liver steatosis was created. Conclusion. Steatometry is to be considered as an important diagnostic method for the prognosis assessment in patients who have risk factors for the development and progression of non-alcoholic metabolic dysfunction-associated fatty liver disease. Severe steatosis is a predictor of steatohepatitis. The number of metabolic factors present in an individual patient is important in assessing the risk of severe liver steatosis and steatohepatitis.

Comorbid pathology in patients with hyperuricemia in the Khabarovsk region

BACKGROUND: Uric acid can affect many metabolic processes in the human body. In recent decades, great importance has been given to increased levels of uric acid — hyperuricemia. Hyperuricemia has been proven to be an independent risk factor for the development of cardiovascular, renal and metabolic diseases, and not just their marker, as had previously ben considered. AIM: To determine the incidence of hyperuricemia at the primary outpatient stage, as well as to assess the prevalence of comorbid pathology among patients with hyperuricemia in the Khabarovsk Territory. MATERIALS AND METHODS: We analyzed 5261 medical records of the patients who applied for an initial outpatient appointment at the Clinical Diagnostic Center and the Viveya Consultative and Diagnostic Center in Khabarovsk from November 2022 to November 2023. From the total number of medical records 2428 patients had elevated level of uric acid in the blood. RESULTS: Arterial hypertension (60.5%) was the most common pathology; obesity – the second (27.35%); diabetes mellitus type 2 was less common in the patients with hyperuricemia (17.75%), and nephrolithiasis was the least common pathology (7.91%). CONCLUSIONS: A high prevalence of hyperuricemia among the population of the Khabarovsk Territory was revealed. Elevated levels of uric acid affect the development of comorbid pathology in the patients, in particular cardiovascular pathology. The results obtained during the study indicate a high prevalence of comorbid diseases in hyperuricemia with arterial hypertension being the most frequent.

Exploring the Gut-Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders.

This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences cellular stress responses through Rac1 activation, Forkhead-type transcription factors inactivation, and mitochondria-mediated apoptosis, alongside modulatory effects of gut microbiota-derived metabolites and endotoxins. Employing an integrative approach, the review synthesizes findings from a broad array of studies, including molecular biology techniques and analyses of microbial metabolites' impacts on host cellular pathways. The results underscore a complex interplay between microbial metabolites, p66Shc activation, and mitochondrial dysfunction, highlighting the significance of the gut microbiome in influencing disease outcomes through oxidative stress pathways. Conclusively, the review posits that targeting the gut microbiota-p66Shc-mitochondrial axis could offer novel therapeutic strategies for mitigating the development and progression of metabolic diseases. This underscores the potential of dietary interventions and microbiota modulation in managing oxidative stress and inflammation, pivotal factors in chronic disease etiology.

Abstract 2169: Dietary inflammatory potential and mortality among patients with MAFLD

Abstract Background: Inflammation is important in metabolic dysfunction-associated fatty liver disease (MAFLD) development and progression. However, evidence regarding the influence of dietary inflammatory potential and mortality among people with MAFLD is rare. This study aimed to elucidate the association of the energy-density dietary inflammatory index (E-DII) with all-cause and cause-specific mortality among MAFLD patients. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) (1988-1994, 1999-2010). MAFLD was defined as the evidence of hepatic steatosis with ≥1 of the following: type 2 diabetes (T2DM), overweight/obesity (OW, BMI ≥ 25 kg/m2), or lean metabolic dysregulation (MD). Dietary intake was assessed through 24-hour dietary recalls. E-DII scores and component intakes were divided into tertiles, with T1 as the reference. Through linkage to National Death Index by December 31, 2019, mortality from all cause, cardiovascular disease (CVD), and cancer were identified. Multivariable Cox proportional hazards regression model and restricted cubic splines (RCS) were used to analyze the association between dietary inflammatory potential and mortality among MAFLD and its subtypes patients. Results: A total of 6537 MAFLD patients were included in the present analysis. During the median follow-up of 16.8 years, 2281 total deaths (534 cancer-related, 750 CVD-related) were documented. Compared to high dietary inflammatory potential, low dietary inflammatory potential presented a inverse association with all-cause mortality risk in MAFLD patients (HR T2 vs. T1 = 0.83, 95% CI = 0.72-0.95, HR T3 vs. T1 = 0.88, 95% CI = 0.76-1.01, P trend = 0.092) and OW subtype patients (HR T2 vs. T1 = 0.77, 95% CI = 0.63-0.93, HR T3 vs. T1 = 0.76, 95% CI = 0.63-0.92, P trend = 0.009). No significant benefit was observed among T2DM and MD subtype patients. Further component analysis found that eicosapentaenoic acid (EPA) (HR = 0.74, 95% CI = 0.66-0.83), docosapentaenoic acid (DPA) (HR = 0.72, 95% CI = 0.65-0.80), docosahexaenoic acid (DHA) (HR = 0.85, 95% CI = 0.65-0.80), and linoleic acid (HR = 0.86, 95% CI = 0.79-0.94) were linked with reduced cancer mortality risk in MAFLD patients. Further RCS analyses found that the effect pattern of EPA, DPA, and DHA on both all-cause and cause-specific mortality was presented as “J shaped” (P non-linear &amp;lt; 0.05). Similar results were observed for all-cause and CVD mortality among both MAFLD and OW subtype patients. When excluding participants who died within five years, consistent results were presented. Conclusions: The findings of this study suggest that keep low-inflammatory dietary pattern, especially appropriate level of PUFAs component (EPA, DPA, and DHA) intake were associated with a lower risk of cancer mortality in MAFLD patients. These findings may inform future public health guidelines regarding specific dietary consumption, and liver-related health promotion. Citation Format: Zhangyan Lyu, Yacong Zhang, Wenxuan Li, Guoijn Si, Kexin Chen. Dietary inflammatory potential and mortality among patients with MAFLD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2169.

The Significance of Lipoproteins in the Development of Obesity.

Disruption of lipoprotein metabolism plays an important role in the development of several cardiovascular, inflammatory, and metabolic diseases. This review examines the importance of different types of lipoproteins and the role they play in the development of dyslipidemia in obesity. The causes and consequences associated with the disruption of lipid metabolism and its significance in the pathogenesis of obesity are considered. The relationship between such pathological processes, which occur alongside obesity as dyslipidemia and inflammation, is determined. In view of the current efficacy and toxicity limitations of currently approved drugs, natural compounds as potential therapeutic agents in the treatment of obesity are considered in the review. The complex mechanisms of lipid metabolism normalization in obesity found for these compounds can serve as one of the confirmations of their potential efficacy in treating obesity. Nanoparticles can serve as carriers for the considered drugs, which can improve their pharmacokinetic properties.

Adipocytokines as Predictors of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Development in Type 2 Diabetes Mellitus Patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common chronic liver condition. Due to pathophysiological processes, MASLD's relation to type 2 diabetes mellitus (T2DM) is still unclear, especially when the role of adipocytokines is taken into consideration. This study aims to examine the potential predictive value of adiponectin and resistin for MASLD in T2DM. In a two-year study, 71 T2DM patients were categorized into MASLD-T2DM and non-MASLD-T2DM groups according to MASLD development. Serum samples were tested for resistin, adiponectin, high-density lipoprotein cholesterol, fasting glucose, and triglycerides. An appropriate equation is used to calculate the adiponectin/resistin (A/R) index. The optimal cut-off values for differentiating MASLD patients from non-MASLD patients were determined using receiver operating characteristic (ROC) curves and the corresponding areas under the curve (AUC). To predict the onset of MASLD in patients with T2DM, a logistic regression analysis was performed. There were significant differences in adiponectin (p<0.001), resistin (p<0.001), and A/R index (p<0.001) between T2DM individuals with and without MASLD. The ROC curve for resistin produced an AUC of 0.997 (p<0.001) with a sensitivity of 96.1% and a specificity of 100% for the cut-off point of 253.15. Adiponectin (OR, 0.054; 95% CI, 0.011-0.268; p<0.001) and resistin (OR, 1.745; 95% CI, 1.195-2,548; p=0.004) were found to be independent predictors for MASLD by logistic regression analysis. This study confirms the potential of adiponectin and resistin as predictors of MASLD development in T2DM.

New insights of DsbA-L in the pathogenesis of metabolic diseases.

Metabolic diseases, such as obesity, diabetes mellitus, and non-alcoholic fatty liver disease (NAFLD), are abnormal conditions that result from disturbances of metabolism. With the improvement of living conditions, the morbidity and mortality rates of metabolic diseases are steadily rising, posing a significant threat to human health worldwide. Therefore, identifying novel effective targets for metabolic diseases is crucial. Accumulating evidence has indicated that disulfide bond A oxidoreductase-like protein (DsbA-L) delays the development of metabolic diseases. However, the underlying mechanisms of DsbA-L in metabolic diseases remain unclear. In this review, we will discuss the roles of DsbA-L in the pathogenesis of metabolic diseases, including obesity, diabetes mellitus, and NAFLD, and highlight the potential mechanisms. These findings suggest that DsbA-L might provide a novel therapeutic strategy for metabolic diseases.