BACKGROUND: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD). METHODS: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation. RESULTS: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08-22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells. CONCLUSIONS Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment.
Animals ; DNA, Mitochondrial/genetics* ; Humans ; Male ; DNA Copy Number Variations ; Female ; Fatty Liver/blood* ; Rats ; Middle Aged ; Longitudinal Studies ; Rats, Sprague-Dawley ; Adult ; Japan/epidemiology* ; Aged ; Biomarkers/blood* ; Hep G2 Cells ; Diet, High-Fat/adverse effects*

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) and hypertension are common metabolic disorders, both closely associated with insulin resistance (IR), suggesting potential shared pathological mechanisms. This study aims to investigate the mediating role of IR in the relationship between hypertension and NAFLD, and to evaluate the applicability and modeling value of various IR surrogate indices in predicting NAFLD risk. METHODS: A total of 280 976 individuals who underwent health examinations at the Health Management Center of the Third Xiangya Hospital of Central South University between August 2017 and December 2021 were included. NAFLD was diagnosed based on abdominal ultrasound findings, and hypertension was defined according to the criteria of the Chinese Guidelines for the Management of Hypertension. Demographic information, anthropometric indices, and biochemical parameters were collected, and multiple IR surrogate indices were constructed, including the triglyceride-glucose index (TyG) and its derivatives, as well as the metabolic score for insulin resistance (METS-IR). Group comparisons were performed between hypertensive and non-hypertensive participants, as well as between NAFLD and non-NAFLD participants. Pearson correlation analysis was applied to assess the associations of metabolic parameters and IR indices with NAFLD. Furthermore, mediation models were constructed to explore the mediating role of IR in the "hypertension-NAFLD" relationship. Finally, parametric models and machine learning algorithms were compared to evaluate their predictive performance and value in assessing NAFLD risk in this population. RESULTS: The prevalence of NAFLD was significantly higher in hypertensive individuals than in non-hypertensive participants (63.61% vs 33.79%, P<0.001), accompanied by elevated IR levels and adverse metabolic features. Correlation analysis and variable importance rankings across multiple models consistently identified TyG-waist circumference (TyG-WC) and METS-IR as the IR indices most strongly associated with NAFLD. In mediation analysis, the TyG-WC pathway explained 32.03% of the total effect, and the METS-IR pathway explained 17.02%. Interaction analysis showed that hypertension status may attenuate the mediating effect of IR (all interaction estimates were negative). In prediction model comparisons, the simplified model incorporating sex, age, WC, TyG-WC, and METS-IR demonstrated good performance in the test set. Logistic regression and its regularized form (LASSO regression) achieved an accuracy of 0.83, receiver operating characteristic (ROC)-area under the curve (AUC) of 0.91, and a Brier score of 0.12, comparable to ensemble models (random forest and XGBoost), with consistently stable performance across different algorithms. CONCLUSIONS IR plays a significant mediating role in the association between hypertension and NAFLD, with TyG-WC identified as a key indicator showing strong mechanistic relevance and predictive value. Risk prediction models based on IR surrogate indices demonstrate advantages in simplicity and interpretability, providing empirical support for the early screening and individualized prevention of NAFLD in the general population.
Humans ; Non-alcoholic Fatty Liver Disease/complications* ; Insulin Resistance ; Hypertension/epidemiology* ; Male ; Female ; Middle Aged ; Risk Factors ; Adult ; Machine Learning ; Triglycerides/blood*

Animals ; Blood Glucose ; Diet, High-Fat/adverse effects* ; Fatty Liver/metabolism* ; Lipid Metabolism ; Lipids/blood* ; Liver/metabolism* ; Mice ; Mice, Knockout, ApoE ; Plant Extracts/pharmacology* ; Raphanus/chemistry* ; Seeds/chemistry*

fatty liver disease (NAFLD) is the most common liver disease which has become a public health concern. Since oxidative stress plays a crucial role in the pathogenesis of NAFLD, subsequent hematological disorders are expected. Therefore, antioxidant compounds such as quercetin could ameliorate the related side-effect of oxidative stress. The aim of the current study was to assess the effect of quercetin on hematological parameters in NAFLD patients. A randomized, double-blind, placebo-controlled trial was conducted as a pilot study. In this study 90 patients with NAFLD were supplemented with either a quercetin or a placebo capsule twice daily (500 mg) for 12 weeks. Blood sample was obtained for laboratory parameters at baseline and the end of week 12. End of trial values for red blood cell (RBC; p = 0.002), mean corpuscular hemoglobin concentration (p = 0.029), and mean platelet volume (p = 0.017), significantly increased and the levels of mean corpuscular volume (MCV; p = 0.023), RBC distribution width-coefficient of variation (p = 0.005), platelet distribution width (p = 0.015), and ferritin (p = 0.002) significantly decreased compared to the baseline in group receiving quercetin. Between group analysis revealed that RBC significantly increased (p = 0.025) but, mean corpuscular volume (p = 0.004), mean corpuscular hemoglobin (MCH; p = 0.002), and ferritin (p = 0.013) significantly decreased compared to placebo group. In this work quercetin showed significant effect on RBC, ferritin, MCV, and MCH in intervention group.TRIAL REGISTRATION: Iranian Center for Clinical Trials Identifier: IRCT2016060628299N1]]>
Anemia ; Blood Platelets ; Erythrocyte Indices ; Erythrocytes ; Ferritins ; Hematology ; Humans ; Inflammation ; Liver Diseases ; Mean Platelet Volume ; Non-alcoholic Fatty Liver Disease ; Oxidative Stress ; Pilot Projects ; Public Health ; Quercetin

Camellia oil has become an important plant oil in China in recent years, but its effects on non-alcoholic fatty liver disease (NAFLD) have not been documented. In this study, the effects of camellia oil, soybean oil, and olive oil on NAFLD were evaluated by analyzing the fatty acid profiles of the plant oils, the serum lipids and lipoproteins of rats fed different oils, and by cytological and ultrastructural observation of the rats' hepatocytes. Analysis of fatty acid profiles showed that the polyunsaturated fatty acid (PUFA) n-6/n-3 ratio was 33.33 in camellia oil, 12.50 in olive oil, and 7.69 in soybean oil. Analyses of serum lipids and lipoproteins of rats showed that the levels of total cholesterol and low-density lipoprotein cholesterol in a camellia oil-fed group (COFG) were lower than those in an olive oil-fed group (OOFG) and higher than those in a soybean oil-fed group (SOFG). However, only the difference in total cholesterol between the COFG and SOFG was statistically significant. Cytological observation showed that the degree of lipid droplet (LD) accumulation in the hepatocytes in the COFG was lower than that in the OOFG, but higher than that in the SOFG. Ultrastructural analysis revealed that the size and number of the LDs in the hepatocytes of rats fed each of the three types of oil were related to the degree of damage to organelles, including the positions of nuclei and the integrity of mitochondria and endoplasmic reticulum. The results revealed that the effect of camellia oil on NAFLD in rats was greater than that of soybean oil, but less than that of olive oil. Although the overall trend was that among the three oil diets, those with a lower n-6/n-3 ratio were associated with a lower risk of NAFLD, and the effect of camellia oil on NAFLD was not entirely related to the n-6/n-3 ratio and may have involved other factors. This provides new insights into the effect of oil diets on NAFLD.
Animals ; Camellia/chemistry* ; Fatty Acids/analysis* ; Hepatocytes/ultrastructure* ; Lipid Droplets/physiology* ; Lipids/blood* ; Male ; Non-alcoholic Fatty Liver Disease/pathology* ; Plant Oils/administration & dosage* ; Rats ; Rats, Sprague-Dawley

BACKGROUND/AIMS: Advanced hepatic fibrosis is associated with cardiovascular disease (CVD) in patients with nonalcoholic fatty liver disease (NAFLD). We investigated the association between noninvasive serum fibrosis markers and the coronary artery calcium score (CACS) in subjects with NAFLD. METHODS: We analyzed 665 NAFLD subjects without chronic liver disease or heart disease between 2011 and 2015. The noninvasive fibrosis markers that were used to evaluate the severity of hepatic fibrosis included the NAFLD fibrosis score (NFS), fibrosis-4 (FIB-4) score, Forn's index, and the aspartate aminotransferase to platelet ratio index (APRI). RESULTS: The areas under the receiver operating characteristics curves for the NFS, FIB-4 score, Forn's index and APRI for predicting CACS >100 were 0.689, 0.683, 0.659, and 0.595, respectively. According to the multivariate analysis, older age, increased body mass index (BMI), and decreased estimated glomerular filtration rate (eGFR) were significant factors associated with CACS >100. The NFS, FIB-4 score and APRI were significantly associated with CACS >100 after adjusting for age and gender (p=0.006, p=0.012, and p=0.012, respectively) and after adjusting for age, gender, BMI and eGFR (p=0.013, p=0.022, and p=0.027, respectively). Scores integrating noninvasive fibrosis markers and other risk factors improved the predictive accuracy. CONCLUSIONS: The NFS and FIB-4 score were associated with coronary atherosclerosis in subjects with NAFLD. Furthermore, scores integrating these noninvasive scores and risk factors for CVD showed good discriminatory power in predicting CACS >100. Therefore, noninvasive serum fibrosis markers may be useful tools for identifying NAFLD subjects at a high risk for CVD.
Aspartate Aminotransferases ; Blood Platelets ; Body Mass Index ; Calcium ; Cardiovascular Diseases ; Coronary Artery Disease ; Coronary Vessels ; Fibrosis ; Glomerular Filtration Rate ; Heart Diseases ; Humans ; Liver Diseases ; Multivariate Analysis ; Non-alcoholic Fatty Liver Disease ; Risk Factors ; ROC Curve

OBJECTIVE: Fatty liver is associated with insulin resistance-related diseases, such as dyslipidemia, obesity, and type 2 diabetes. The aim of this study was to evaluate the association of dyslipidemia with fatty liver and assess the differences in these associations according to the degree of hepatic steatosis. METHODS: A total of 2,462 subjects (1,679 men and 783 women) who underwent a comprehensive health check-up (including abdominal computed tomography) from January 2010 to December 2013 were enrolled at Samsung Changwon Hospital Healthcare Center. The liver attenuation index (LAI), defined as the difference between mean hepatic and splenic attenuation, was used to assess the degree of hepatic steatosis. An LAI below 5 Hounsfield units was defined as fatty liver. RESULTS: We found that 32.2% of the study subjects had fatty liver. Serum low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG), and fasting blood glucose concentrations and glycated hemoglobin (HbA1c percentage) were significant greater in the fatty liver group compared with the non-fatty liver group, while serum high-density lipoprotein cholesterol (HDL-C) was significantly lower in the fatty liver group. Subjects with fatty liver had 1.7-fold greater risk of dyslipidemia than those without fatty liver after adjusting for age, sex, body mass index (BMI), and HbA1c. When individuals with fatty liver were analyzed by tertiles of LAI values, LDL-C, TG, fasting glucose, BMI, and HbA1c concentrations increased while HDL-C decreased with decreasing LAI tertiles. Compared with LAI tertile 3, the risk for dyslipidemia significantly increased with adjusted odds ratios of 1.42, and 1.81 in tertiles 2 and 1, respectively. CONCLUSION: Fatty liver was significantly associated with dyslipidemia and this association varied according to the degree of hepatic steatosis.
Blood Glucose ; Body Mass Index ; Cholesterol ; Delivery of Health Care ; Dyslipidemias ; Fasting ; Fatty Liver ; Glucose ; Gyeongsangnam-do ; Hemoglobin A, Glycosylated ; Humans ; Insulin ; Korea ; Lipoproteins ; Liver ; Male ; Obesity ; Odds Ratio ; Tomography, Spiral Computed ; Triglycerides

OBJECTIVE: Penetrating brain trauma (PBT) caused by gunshot is one of the most lethal traumatic brain injuries (TBIs) and its management and confrontation is of great importance. METHODS: The authors searched retrospectively the archives from 2 similar autonomous laboratories of forensic science and toxicology in the Balkan peninsula for a 10-year period of time and included only fatal penetrating brain injuries. RESULTS: The study is conducted in 61 cadavers with gunshot PBT. All of the cadavers were victims of suicide attempt. The most common anatomical localization on the skull were the facial bones, followed by skull base, temporal and parietal bone, conducting a trajectory of the gunshot. Additional findings were atherosclerosis of the blood vessels and chronic diseases such as chronic obstructive pulmonary disease, cancer and fatty liver. CONCLUSION: PBI has a high mortality rate. There are factors and findings from the collected data differing between the 2 aforementioned nations. Either way, better preventative measures, gun control and healthcare system are highly necessary.
Atherosclerosis ; Balkan Peninsula ; Blood Vessels ; Brain Injuries ; Brain ; Bulgaria ; Cadaver ; Chronic Disease ; Delivery of Health Care ; Ethnic Groups ; Facial Bones ; Fatty Liver ; Forensic Sciences ; Greece ; Head Injuries, Penetrating ; Humans ; Mortality ; Parietal Bone ; Pulmonary Disease, Chronic Obstructive ; Retrospective Studies ; Skull ; Skull Base ; Suicide ; Toxicology ; Wounds, Gunshot

OBJECTIVE: To investigate the relationship between serum 25(OH) vitamin D and liver fat content in nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 120 patients with NAFLD admitted in our hospital between June and August, 2017 were enrolled and divided into 4 groups with different serum 25 (OH) vitamin D levels: >75 nmol/L (group A, =25), 50-75 nmol/L (group B, =35), 25-50 nmol/L (group C, =32), and < 25 nmol/L (group D, =28). For all the patients, serum 25 (OH) vitamin D level was measured by ELISA, and liver fat content was determined using in-phase opposed-phase TWI sequences. The measurement data were compared among the 4 groups to assess the association between serum 25(OH) vitamin D level and liver fat content. RESULTS: The liver fat content appeared to be higher in group B (28.66±6.45%) and group C (38.74±11.47%) than in group A (22.79 ± 6.10%), but the difference was not statistically significant (>0.05); the liver fat content in group D (54.79 ± 5.28%) was significantly higher than that in the other 3 groups (>0.05). Liver fat content increased significantly as serum 25(OH) vitamin D level decreased, showing an inverse correlation between them in these patients ( < 0.05, =-0.125). CONCLUSIONS In patients with NAFLD, a decreased serum 25(OH) vitamin D level is associated with an increased liver fat content, suggesting the value of serum 25(OH) vitamin D as a predictor of NAFLD.
Humans ; Liver ; pathology ; Non-alcoholic Fatty Liver Disease ; blood ; pathology ; Vitamin D ; blood

BACKGROUND/AIMS: Fatty liver is a clinical and pathologic condition in individuals with type 2 diabetes (T2D). The purpose of this study is to examine the effects of different exercise modalities on non-alcoholic fatty liver indices (fatty liver index [FLI], lipid accumulation product [LAP], hepatic steatosis index [HSI], and Framingham Steatosis Index [FSI]) in women with T2D. METHODS: Fifty-two women with T2D and a mean age of 55.07±5.92 yrs, body mass index (BMI) 28.94±4.09 kg/m² , and hemoglobin A1c (HbA1c) 9.41±0.82% were randomized to a sprint interval training (SIT) (n=17), combined aerobic and resistance (A+R) training (n=17), or control group (n=18) for 10 weeks. Two-way repeated analysis of variance (ANOVA) was used to find differences between groups and the effects of time and Time×Group interactions after 10 weeks on non-alcoholic fatty liver indices. After this, ANOVA models were constructed to determine the effects of group allocation and change in non-alcoholic fatty liver indices. RESULTS: There were significant time interactions for FLI (P<0.001), HSI (P<0.001), and LAP (P<0.001). Also, there were significant Time×Group interactions for fasting blood glucose (P=0.034), and HbA1c (P=0.006). CONCLUSIONS: Results highlight that exercise training, independent of mode of training, is an effective strategy to improve some indices related to hepatic steatosis and blood glucose profiles in women with T2D.
Blood Glucose ; Body Mass Index ; Diabetes Mellitus, Type 2 ; Fasting ; Fatty Liver ; Female ; Humans ; Lipid Accumulation Product ; Liver ; Non-alcoholic Fatty Liver Disease ; Overweight