Studies in heterogeneous groups of people with respect to sex, body mass index (BMI), and glycemic status (normoglycemia, impaired glucose tolerance, diabetes), indicate no relationship between liver fat accumulation and pancreatic insulin secretion.

This work aimed to better understand the association of liver fat with insulin secretion.

A cross-sectional analysis was conducted of 61 men with abdominal obesity who had high liver fat (HLF, ≥ 5.6% by magnetic resonance spectroscopy, n = 28) or low liver fat (LLF, n = 33), but were balanced on BMI, total body fat, visceral adipose tissue (VAT), and pancreatic fat. A frequently sampled 5-hour oral glucose tolerance test with 11 samples, in conjunction with mathematical modeling, was used to compute indices of insulin sensitivity and insulin secretion (oral minimal model).

Compared to individuals with LLF, those with HLF had significantly greater fasting glucose, insulin, C-peptide, and triglycerides; lower high-density lipoprotein cholesterol; but similar glycated hemoglobin A1c. Areas under the 5-hour curve for glucose, insulin, and C-peptide were greater in the HLF group than the LLF group (by ∼10%, ∼38%, and ∼28%, respectively); fasting and total postprandial insulin secretion rates were approximately 37% and approximately 50% greater, respectively (all P < .05); whereas the insulinogenic index was not different. HLF participants had lower whole-body and hepatic insulin sensitivity, disposition index, and total insulin clearance than LLF participants (all P < .05).

Accumulation of liver fat is associated with increased insulin secretion independently of total adiposity, abdominal fat distribution, and pancreatic fat. Thereby, hyperinsulinemia in fatty liver disease is partly because of insulin hypersecretion and partly because of impaired insulin clearance.

Metabolic-associated fatty liver disease (MAFLD) is the predominant form of chronic liver disease worldwide. This study was designed to investigate the proportion and characteristics of MAFLD within the general Chinese population and to identify the contributory risk factors for liver fibrosis among MAFLD individuals.

The participants were recruited from a cohort undergoing routine health evaluations at the Third Hospital of Hebei Medical University between May 2019 and March 2023. The diagnosis of MAFLD was based on the established clinical practice guidelines. The fibrosis-4 index score (FIB-4) was employed to evaluate hepatic fibrosis, with a FIB-4 score of ≥1.3 indicating significant fibrosis. Binary logistic regression analyses were used to determine risk factors associated with significant hepatic fibrosis in MAFLD.

A total of 22,970 participants who underwent comprehensive medical examinations were included in the analysis. The overall proportion of MAFLD was 28.77% (6608/22,970), with 16.87% (1115/6608) of these patients showing significant fibrosis as assessed using FIB-4. Independent risk factors for significant liver fibrosis in MAFLD patients were male (odds ratio [OR] = 0.676, 95% confidence interval [CI]: 0.558-0.821), hepatitis B surface antigen (HBsAg) positivity (OR = 2.611, 95% CI: 1.557-4.379), body mass index ≥23.00 kg/m 2 (OR = 0.632, 95% CI: 0.470-0.851), blood pressure ≥130/85 mmHg (OR = 1.885, 95% CI: 1.564-2.272), and plasma glucose ≥5.6 mmol/L (OR = 1.815, 95% CI: 1.507-2.186) (all P <0.001).

The proportion of MAFLD in an urban Chinese population is 28.77%. About 16.87% of MAFLD patients presented with significant liver fibrosis. Independent risk factors for significant liver fibrosis in MAFLD patients should be noticed.

Background Epidemiological evidence has indicated that insulin resistance (IR), as measured by a homeostatic model assessment for IR (HOMA-IR), is strongly correlated with body mass index (BMI). However, there is a paucity of studies assessing the complex interaction between BMI and HOMA-IR with respect to all-cause mortality, particularly among Asian individuals without diabetes. Materials and methods The research centered on individuals diagnosed without diabetes, comprising 881 men with a mean age of 62 years (± standard deviation (SD): 14) and 1,159 women with a mean age of 64 years (± 11). The participants were drawn from the Nomura cohort study, consisting of two cohorts: one initiated in 2002 and the other in 2014. To assess the risk of all-cause mortality up to the end of the follow-up period, we applied a Cox proportional hazards model, adjusting for a range of covariates to calculate the hazard ratios (HRs). Results Participants were followed for a median duration of 7,691 days (interquartile range: 4,235-7,761 days). Over the course of the follow-up period, a total of 672 deaths were documented, comprising 338 deaths among men and 334 among women. The interaction between BMI and HOMA-IR (HR: 1.05; 95% confidence interval (CI): 1.02-1.09) was significantly associated with all-cause mortality, along with gender, age, BMI, history of cardiovascular disease, hyperuricemia, and HOMA-IR. Moreover, the HRs for all-cause mortality were examined for each BMI group by dividing the HOMA-IR by one SD. In the BMI < 22.0 kg/m² group, using the third HOMA-IR as the reference, significant HR (J curve) increases were observed in the first, second, and fourth HOMA-IR. In the BMI ≥ 22.0 kg/m² group, using the first HOMA-IR as the reference, a significant increase in HR was observed only in the fourth HOMA-IR. An interaction between BMI and HOMA-IR was identified for all-cause mortality (p = 0.005). Conclusions BMI confounds the association between IR, as measured by HOMA-IR, and the risk of all-cause mortality among Japanese individuals.

Excessive high-fat diet (HFD) intake can precipitate metabolic dysfunction-associated fatty liver disease (MAFLD). Tangeretin is a citrus flavonoid possessing many biological properties. We examined the impact of tangeretin on MAFLD and its underlying mechanism. Rats were given HFD plus 15% fructose solution for four months to produce metabolic syndrome. Metabolic syndrome rats were administered 100 mg/kg of metformin or 25 mg/kg of tangeretin for the last four weeks. HFD-induced increased body weight, liver weight, adipose tissue weight, fasting blood glucose, serum insulin, total triglyceride, total cholesterol, and free fatty acids and reduced adiponectin and high-density lipoprotein cholesterol levels in metabolic syndrome, which were alleviated by tangeretin (p < 0.05). Tangeretin stabilized alanine transaminase activity, liver catalase, and inflammatory and oxidative stress markers in HFD rats compared to untreated HFD rats (p < 0.05). Tangeretin reduced hepatic steatosis induced by HFD. Downregulation of hepatic insulin receptor substrate-1 (IRS-1) and protein kinase B (Akt) protein expression in metabolic syndrome rats was recovered by tangeretin (p < 0.05). Metformin, an antihyperglycemic drug, produced comparable effects to tangeretin. In conclusion, tangeretin attenuates metabolic disorders and fatty liver induced by HFD in rats. The underlying mechanisms involve reducing oxidative stress, and inflammation and enhancing insulin sensitivity.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease, represents a prevalent condition ranging from simple steatosis to advanced stages associated with liver cancer. Asymptomatic presentation in the majority of cases underscores the need for non-invasive, cost-effective methods to stratify degree of hepatic steatosis. This cross-sectional study aimed to assess the association between obesity and lipid-related indices with the degree of hepatic steatosis in MASLD patients. 150 individuals recently diagnosed with metabolic dysfunction-associated steatotic liver disease were recruited. Anthropometric measurements, including weight, height, and waist circumference (WC), were taken, alongside biochemical parameters such as alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides (TG), high-density lipoprotein, low-density lipoprotein, and fasting plasma glucose, following a 12-h fasting period. Various indicators of obesity and lipid metabolism, including body mass index, waist-to-height ratio (WHtR), a body shape index, lipid accumulation product (LAP), triglyceride-glucose index (TyG), visceral adiposity index, and hepatic steatosis index (HSI), were calculated. The diagnosis of MASLD and degree of hepatic steatosis were established through abdominal ultrasound examination. Data analysis was performed utilizing SPSS version 22. All the investigated indices displayed an area under the curve (AUC) surpassing 0.5, implying a correlation with the degree of hepatic steatosis. Notably, TyG-WC, TyG-WHtR, LAP, and a cardiometabolic obesity index showed the highest AUC values (> 0.7), indicating a relatively strong association with degree of hepatic steatosis. Specifically, in females, TyG-WC (AUC = 0.797, 95% CI 0.712-0.882, threshold = 865.991), while in males, LAP (AUC = 0.746, 95% CI 0.593-0.899, threshold = 74.290), demonstrated the highest AUC values. TyG-WHtR, TyG-WC, and LAP exhibited significant correlations with the degree of hepatic steatosis. Given their non-invasive nature and easy measurement, they hold promise for potential clinical utility, pending validation in additional studies.

NAFLD is a rapidly expanding global health issue that is distinguished by the accumulation of hepatic fat that is not associated with alcohol consumption. Parallel to the increase in obesity and type 2 diabetes mellitus (T2DM), its prevalence is also increasing. Amidst a backdrop of limited epidemiological data, Somalia, which is undergoing urbanization and dietary adjustments, is contending with escalating rates of NAFLD. Our study aims to addresses critical voids in local epidemiological data regarding this subject in Somalia.

The objective of this retrospective study was to evaluate the prevalence of NAFLD and concomitant risk factors among T2DM patients at the Mogadishu Somalia Turkish Training and Research Hospital. A total of 832 patients diagnosed with T2DM between May 2023 and March 2024 were used to analyze the data. Various variables, such as age, sex, diabetic medications, hypertension, insulin resistance, hyperlipidemia, and NAFLD grade, were obtained from electronic medical records. Statistical analyses were conducted to investigate the associations and predictors of NAFLD using descriptive analysis, logistic regression, and multiple regression.

The study cohort was predominately female (57%), with a mean age of 53.48 years. The most prevalent grades of NAFLD were grade 1 and grade 2, with NAFLD being identified in 53.8% of patients. NAFLD displayed a robust correlation with insulin resistance (OR: 52.04), with hypertension (OR: 20.091) and hyperlipidemia (OR: 2.528) following shortly thereafter. These factors collectively account for 57% of the variance in NAFLD, as indicated by multiple regression analysis (R2 = 0.57, F (6,823) = 184.302, p < 0.001).

This investigation emphasizes the presence of a high prevalence of NAFLD among T2DM patients in Mogadishu, Somalia, 53.8% which is substantially influenced by hypertension, insulin resistance, and hyperlipidemia. In this region, the necessity of targeted healthcare strategies to mitigate metabolic liver diseases is underscored by the results.

This study aimed to assess the relationship between regional body composition and metabolic dysfunction-associated fatty liver disease (MAFLD) in Chinese children.

In this study, 1399 children aged 7-14 years were included. Liver steatosis was assessed using the controlled attenuation parameter (CAP) measured through Fibroscan. MAFLD is defined as the presence of liver steatosis along with either overweight/obesity, prediabetes/diabetes, or at least two metabolic index abnormalities. Regression analyses were applied to assess the relationship between regional body composition and MAFLD in children. Subgroup analyses were performed based on sex and weight.

The participants had a mean age of 9 years, with 52.11% being boys. Among them, 134 (9.57%) were diagnosed with MAFLD, and 17 (1.22%) had severe fatty liver disease. We found an inverse correlation between the muscle percentage in each region and MAFLD, with the extremities demonstrating the most significant negative correlation (OR: 0.732; 95% CI: 0.634-0.844). Conversely, regional fat was positively associated with MAFLD, with the strongest correlation found in the upper limbs (OR: 3.104; 95% CI: 2.023-4.764). Subgroup analyses showed similar results.

The decrease in regional muscle percentage, particularly in the limbs, along with the increase in regional fat percentage, especially in the upper limbs, is associated with a higher probability of developing MAFLD in prepubertal children. Additional prospective studies are needed to strengthen and validate these findings.

Ginsenoside Rg1 (GRg1), a key bioactive component of medicinal herbs, has shown beneficial effects on non-alcoholic fatty liver disease (NAFLD) and numerous other conditions. Nevertheless, the specific targets that are actively involved and the potential mechanisms underlying NAFLD treatment remain unclear. This study aimed to elucidate the therapeutic effects and mechanism of GRg1 in alleviating NAFLD using a combined approach of network pharmacology and molecular biology validation. The analysis yielded 294 targets for GRg1 and 1293 associated with NAFLD, resulting in 89 overlapping targets. Through protein-protein interactions (PPI) network topology analysis, 10 key targets were identified. Upon evaluating the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analysis, GRg1 may exert therapeutic effects on NAFLD by negatively regulating the apoptotic process, insulin and endocrine resistance, the AGE-RAGE signaling pathway in diabetic complications, and the Estrogen, PI3K/Akt, and MAPK pathways. The three differential gene targets for Akt1, EGFR, and IGF1 were identified through the compound-target network in conjunction with the aforementioned methods. The molecular docking and molecular dynamics (MD) simulations showed that AKT1 and EGFR had a strong binding affinity with GRg1. Overall, our findings point to a novel therapeutic strategy involving NAFLD, with further in vivo and in vitro studies promising to deepen our comprehension and validate its potential advantages.Communicated by Ramaswamy H. Sarma.

A growing body of evidence emphasizes the role of glycemic variability (GV) in the development of conventional diabetes-related complications. Furthermore, advancements in diabetes management and increased life expectancy have led to the emergence of new complications, such as cancer, liver disease, fractures, infections, and cognitive dysfunction. GV is considered to exacerbate oxidative stress and inflammation, acting as a major mechanism underlying these complications. However, few reviews have synthesized the association between GV and these emerging complications or examined their underlying mechanisms. Hence, this narrative review provides a comprehensive discussion of the burden, risks, and mechanisms of GV in these complications, offering further evidence supporting GV as a potential therapeutic target for diabetes management.

Insulin resistance (IR) is one of the important causes of metabolic dysfunction-associated steatotic liver disease (MASLD). Apolipoprotein A-I (apoA-I) is secreted primarily by hepatocytes and plays an essential role in reverse cholesterol transport. Our previous studies revealed that apoA-I can mitigate the progression of metabolic dysfunction-associated steatohepatitis (MASH). However, there is no clear evidence to explain the relationship between apoA-I and IR. Here, we investigated the effects of apoA-I overexpression on IR in both HepG2 cells and mice. In vitro experiment results revealed that apoA-I overexpression can promote cellular glucose uptake in oleic acid-induced IR in HepG2 cells. High-fat, high-cholesterol, and high-fructose diets were used to induce IR in mice. The results showed that apoA-I overexpression improved glucose tolerance, reduced serum insulin levels, and ameliorated IR in diet-induced MASLD mice. Moreover, apoA-I promoted the expression of peroxisome proliferator-activated receptor α (PPARα) in the nucleus both in vitro and in vivo. In conclusion, apoA-I could alleviate MASLD by reducing IR in mice and might exert this effect through the PPARα pathway.

Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.

Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are de novo lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-2H2-glucose, U-2H5-glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2-F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH.

We assessed in vivo rates of hepatic mitochondrial oxidation, gluconeogenesis, and β-hydroxybutyrate (β-OHB) turnover by positional isotopomer NMR tracer analysis (PINTA) in individuals with metabolic-dysfunction-associated steatotic liver (MASL) (fatty liver) and MASL disease (MASLD) (steatohepatitis) compared with BMI-matched control participants with no hepatic steatosis. Hepatic fat content was quantified by localized 1H magnetic resonance spectroscopy (MRS). We found that in vivo rates of hepatic mitochondrial oxidation were unaltered in the MASL and MASLD groups compared with the control group. A physiological increase in plasma glucagon concentrations increased in vivo rates of hepatic mitochondrial oxidation by 50%-75% in individuals with and without MASL and increased rates of glucose production by ∼50% in the MASL group, which could be attributed in part to an ∼30% increase in rates of mitochondrial pyruvate carboxylase flux. These results demonstrate that (1) rates of hepatic mitochondrial oxidation are not substantially altered in individuals with MASL and MASLD and (2) glucagon increases rates of hepatic mitochondrial oxidation.

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements.

Following medical diagnosis of MASH, individuals were randomized to treatment (n = 16) or control (n = 8). Liver fat (magnetic resonance spectroscopy), 18-hour plasma biochemical measurements, and isotopically labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO2peak) were also measured mid-intervention. Those in the treatment group were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Controls continued physician-directed care.

Treatment induced significant (p <0.05) reductions in body weight, fat mass, and liver injury, while VO2peak (p <0.05) and non-esterified fatty acid suppression (p = 0.06) were improved. Both groups exhibited reductions in total energy intake, hemoglobin A1c, hepatic insulin resistance, and liver fat (p <0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO2peak and resolution of liver disease.

Exercise and energy restriction elicited significant and clinically meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH.

The mechanisms that underpin histologic improvement in individuals with metabolic dysfunction-associated steatohepatitis (MASH) are not well understood. This study evaluated the relationship between liver and metabolic health, testing how changes in one may affect the other. We investigated the effects of energy restriction and exercise on the association between multi-tissue insulin sensitivity and histologic improvements in participants with biopsy-proven MASH. For the first time, these results show that an improvement in peripheral (but not hepatic) insulin sensitivity and systemic markers of muscle function (i.e. cardiorespiratory fitness) were strongly related to resolution of liver disease. Extrahepatic disposal of substrates and improved fitness levels supported histologic improvement, confirming the addition of exercise as crucial to lifestyle interventions in MASH.

NCT03151798.

Melanocortins mediate their biological functions via five different melanocortin receptors (MC1R - MC5R). MC1R is expressed in the skin and leukocytes, where it regulates skin pigmentation and inflammatory responses. MC1R is also present in the liver and white adipose tissue, but its functional role in these tissues is unclear. This study aimed at determining the regulatory role of MC1R in fatty acid metabolism.

Male recessive yellow (Mc1re/e) mice, a model of global MC1R deficiency, and male hepatocyte-specific MC1R deficient mice (Mc1r LKO) were fed a chow or Western diet for 12 weeks. The mouse models were characterized for body weight and composition, liver adiposity, adipose tissue mass and morphology, glucose metabolism and lipid metabolism. Furthermore, qPCR and RNA sequencing analyses were used to investigate gene expression profiles in the liver and adipose tissue. HepG2 cells and primary mouse hepatocytes were used to study the effects of pharmacological MC1R activation.

Chow- and Western diet-fed Mc1re/e showed increased liver weight, white adipose tissue mass and plasma triglyceride (TG) concentration compared to wild type mice. This phenotype occurred without significant changes in food intake, body weight, physical activity or glucose metabolism. Mc1r LKO mice displayed a similar phenotype characterized by larger fat depots, increased adipocyte hypertrophy and enhanced accumulation of TG in the liver and plasma. In terms of gene expression, markers of de novo lipogenesis, inflammation and apoptosis were upregulated in the liver of Mc1r LKO mice, while enzymes regulating lipolysis were downregulated in white adipose tissue of these mice. In cultured hepatocytes, selective activation of MC1R reduced ChREBP expression, which is a central transcription factor for lipogenesis.

Hepatocyte-specific loss of MC1R disturbs fatty acid metabolism in the liver and leads to an obesity phenotype characterized by enhanced adipocyte hypertrophy and TG accumulation in the liver and circulation.

Growth differentiation factor 15 (GDF15) is a cell stress-response cytokine within the transforming growth factor-β (TGFβ) superfamily. It is known to exert diverse effects on many metabolic pathways through its receptor GFRAL, which is expressed in the hindbrain, and transduces signals through the downstream receptor tyrosine kinase Ret. Since the liver is the core organ of metabolism, summarizing the functions of GDF15 is highly important. In this review, we assessed the relevant literature regarding the main metabolic, inflammatory, fibrogenic, tumorigenic and other effects of GDF15 on different liver diseases, including Metabolic dysfunction-associated steatotic liver disease(MASLD), alcohol and drug-induced liver injury, as well as autoimmune and viral hepatitis, with a particular focus on the pathogenesis of MASLD progression from hepatic steatosis to MASH, liver fibrosis and even hepatocellular carcinoma (HCC). Finally, we discuss the prospects of the clinical application potential of GDF15 along with its research and development progress. With better knowledge of GDF15, increasing in-depth research will lead to a new era in the field of liver diseases.

We have previously demonstrated that dietary saturated fatty acids (SFA), when compared to polyunsaturated fatty acids (PUFA), are preferentially partitioned into oxidation pathways. However, it remains unclear if this preferential handling is maintained when hepatocellular metabolism is shifted toward fatty acid (FA) esterification and away from oxidation, such as when hepatic de novo lipogenesis (DNL) is upregulated.

To investigate whether an acute upregulation of hepatic DNL influences dietary FA partitioning into oxidation pathways.

20 healthy volunteers (11 females) underwent a fasting baseline visit followed by two study days, 2-weeks apart. Prior to each study day, participants consumed an isocaloric high-carbohydrate diet (to upregulate hepatic DNL) for 3-days. On the two study days, participants consumed an identical standardised test meal that contained either [U13C]palmitate or [U13C]linoleate, in random order, to trace the fate of dietary FA. Blood and breath samples were collected over a 6h postprandial period and 13C enrichment in breath CO2 and plasma lipid fractions were measured using gas-chromatography-combustion-isotope ratio mass spectrometry.

Compared to the baseline visit, fasting plasma triglyceride concentrations and markers of hepatic DNL, the lipogenic and stearyl-CoA desaturase indices, were significantly (p < 0.05) increased after consumption of the high-carbohydrate diet. Appearance of 13C in expired CO2 and tracer recovery were significantly (p < 0.05) higher after consumption of the meal containing [U13C]linoleate compared to [U13C]palmitate (5.1 ± 0.5% vs. 3.7 ± 0.4%), respectively. Incorporation of 13C into the plasma triglyceride and non-esterified fatty acid pool was significantly (p < 0.001) greater for [U13C]palmitate compared to [U13C]linoleate.

Dietary PUFA compared to SFA appear to be preferentially partitioned into oxidation pathways during an acute upregulation of hepatic DNL, thus consumption of a PUFA-enriched diet may help mitigate intrahepatic triglyceride accumulation in individuals at risk of cardiometabolic disease.

Obesity, non-alcoholic fatty liver disease (NAFLD), and atherosclerotic cardiovascular diseases are common and growing public health concerns. Previous epidemiological studies unfolded the robust correlation between obesity, NAFLD, and atherosclerotic cardiovascular diseases. Obesity is a well-known risk factor for NAFLD, and both of them can markedly increase the odds of atherosclerotic cardiovascular diseases. On the other hand, significant weight loss achieved by lifestyle modification, bariatric surgery, or medications, such as semaglutide, can concomitantly improve NAFLD and atherosclerotic cardiovascular diseases. Therefore, certain pathophysiological links are involved in the development of NAFLD in obesity, and atherosclerotic cardiovascular diseases in obesity and NAFLD. Moreover, recent studies indicated that simultaneously targeting several mechanisms by tirzepatide and retatrutide leads to greater weight loss and markedly improves the complications of metabolic syndrome. These findings remind the importance of a mechanistic viewpoint for breaking the association between obesity, NAFLD, and atherosclerotic cardiovascular diseases. In this review article, we mainly focus on shared pathophysiological mechanisms, including insulin resistance, dyslipidemia, GLP1 signaling, inflammation, oxidative stress, mitochondrial dysfunction, gut dysbiosis, renin-angiotensin-aldosterone system (RAAS) overactivity, and endothelial dysfunction. Most of these pathophysiological alterations are primarily initiated by obesity. The development of NAFLD further exacerbates these molecular and cellular alterations, leading to atherosclerotic cardiovascular disease development or progression as the final manifestation of molecular perturbation. A better insight into these mechanisms makes it feasible to develop new multi-target approaches to simultaneously unhinge the deleterious chain of events linking obesity and NAFLD to atherosclerotic cardiovascular diseases.

Chronic hepatitis C virus (HCV) infection is associated with an increased risk of extrahepatic cancers, particularly non-Hodgkin lymphoma. The introduction of direct-acting antivirals (DAAs) has revolutionized HCV therapy, resulting in high cure rates. However, concerns have been raised about potential effects on cancer risk. This review summarizes the current evidence on extrahepatic cancer risk in HCV-infected patients treated with DAAs. We examined epidemiologic data on HCV-associated extrahepatic cancers and explored potential mechanisms linking HCV to carcinogenesis outside the liver. Studies evaluating cancer outcomes after DAA therapy were critically reviewed while considering methodological challenges. While some studies suggested a reduced risk of extrahepatic cancers after DAA therapy, others showed no significant change. Limitations included short follow-up periods and confounding variables. Immunological changes following rapid HCV clearance may have complex effects on cancer risk. Long-term prospective studies and mechanistic investigations are needed to fully elucidate the relationship between DAA therapy and extrahepatic cancer risk in HCV patients. Clinicians should remain vigilant for extrahepatic malignancies in this population.

Nonalcoholic fatty liver disease (NAFLD) is fatty liver mainly related to metabolic syndrome. NAFLD with inflammation and hepatocellular damage is defined as nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. We have previously reported that a hexane insoluble fraction from an anthocyanin-rich purple rice ethanolic extract (PRE-HIF) can suppress prostate carcinogenesis. However, the extract's effect on NASH has not yet been established. In the present study, we investigated the chemopreventive effect of a PRE-HIF on NASH and liver fibrosis using a connexin 32 (Cx32) dominant negative transgenic (Cx32ΔTg) rat NASH model. Seven-week-old male Cx32ΔTg rats were fed a control diet, a high-fat diet (HFD), or an HFD with 1% PRE-HIF and intraperitoneal administration of dimethylnitrosamine for 17 weeks. Histological findings of NASH such as fat deposition, lobular inflammation, hepatocyte ballooning injury, and bridging fibrosis were observed in the HFD group but not in the control group, and all histological parameters were significantly improved by PRE-HIF treatment. Corresponding to the histological changes, increased expression of inflammatory cytokine mRNAs (TNF-α, IL-6, IL-18, IFN-γ, IL-1β, TGF-β1, TIMP1, TIMP2, COL1A1), along with and activation of nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) signaling were observed in the HFD group, which was significantly decreased by PRE-HIF. The number and area of hepatic precancerous glutathione S-transferase placental form-positive foci tended to be decreased by PRE-HIF. These results indicate that intake of purple rice as a dietary supplement may reduce steatohepatitis, liver injury, and fibrosis in NASH by inactivation of NF-κB or JNK.

Current research on metabolic disorders and diabetes relies on animal models because multi-organ diseases cannot be well studied with standard in vitro assays. Here, we have connected cell models of key metabolic organs, the pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based in vitro system. Aided by mechanistic mathematical modeling, we demonstrate that hyperglycemia and high cortisone concentration induce glucose dysregulation in the pancreas-liver microphysiological system (MPS), mimicking a diabetic phenotype seen in patients with glucocorticoid-induced diabetes. In this diseased condition, the pancreas-liver MPS displays beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic gene expression. Conversely, a physiological culture condition maintains glucose tolerance and beta-cell function. This method was reproducible in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic proteins, as demonstrated with a combined transcriptome and proteome analysis.

Nonalcoholic fatty liver disease (NAFLD) is a liver condition that is prevalent worldwide and associated with significant health risks and economic burdens. As it has been linked to insulin resistance (IR), this study aimed to perform a bibliometric analysis and visually represent the scientific literature on IR and NAFLD.

To map the research landscape to underscore critical areas of focus, influential studies, and future directions of NAFLD and IR.

This study conducted a bibliometric analysis of the literature on IR and NAFLD indexed in the SciVerse Scopus database from 1999 to 2022. The search strategy used terms from the literature and medical subject headings, focusing on terms related to IR and NAFLD. VOSviewer software was used to visualize research trends, collaborations, and key thematic areas. The analysis examined publication type, annual research output, contributing countries and institutions, funding agencies, journal impact factors, citation patterns, and highly cited references.

This analysis identified 23124 documents on NAFLD, revealing a significant increase in the number of publications between 1999 and 2022. The search retrieved 715 papers on IR and NAFLD, including 573 (80.14%) articles and 88 (12.31%) reviews. The most productive countries were China (n = 134; 18.74%), the United States (n = 122; 17.06%), Italy (n = 97; 13.57%), and Japan (n = 41; 5.73%). The leading institutions included the Università degli Studi di Torino, Italy (n = 29; 4.06%), and the Consiglio Nazionale delle Ricerche, Italy (n = 19; 2.66%). The top funding agencies were the National Institute of Diabetes and Digestive and Kidney Diseases in the United States (n = 48; 6.71%), and the National Natural Science Foundation of China (n = 37; 5.17%). The most active journals in this field were Hepatology (27 publications), the Journal of Hepatology (17 publications), and the Journal of Clinical Endocrinology and Metabolism (13 publications). The main research hotspots were "therapeutic approaches for IR and NAFLD" and "inflammatory and high-fat diet impacts on NAFLD".

This is the first bibliometric analysis to examine the relationship between IR and NAFLD. In response to the escalating global health challenge of NAFLD, this research highlights an urgent need for a better understanding of this condition and for the development of intervention strategies. Policymakers need to prioritize and address the increasing prevalence of NAFLD.

Previous studies, including Mendelian randomization (MR), have demonstrated type 2 diabetes (T2D) and glycemic traits are associated with increased risk of metabolic dysfunction-associated steatotic liver disease (MASLD). However, few studies have explored the underlying pathway, such as the role of iron homeostasis.

We used a two-step MR approach to investigate the associations of genetic liability to T2D, glycemic traits, iron biomarkers, and liver diseases. We analyzed summary statistics from various genome-wide association studies of T2D (n = 933,970), glycemic traits (n ≤ 209,605), iron biomarkers (n ≤ 246,139), MASLD (n ≤ 972,707), and related biomarkers (alanine aminotransferase (ALT) and proton density fat fraction (PDFF)). Our primary analysis was based on inverse-variance weighting, followed by several sensitivity analyses. We also conducted mediation analyses and explored the role of liver iron in post hoc analysis.

Genetic liability to T2D and elevated fasting insulin (FI) likely increased risk of liver steatosis (ORliability to T2D: 1.14 per doubling in the prevalence, 95% CI: 1.10, 1.19; ORFI: 3.31 per log pmol/l, 95% CI: 1.92, 5.72) and related biomarkers. Liability to T2D also likely increased the risk of developing liver cirrhosis. Genetically elevated ferritin, serum iron, and liver iron were associated with higher risk of liver steatosis (ORferritin: 1.25 per SD, 95% CI 1.07, 1.46; ORliver iron: 1.15 per SD, 95% CI: 1.05, 1.26) and liver cirrhosis (ORserum iron: 1.31, 95% CI: 1.06, 1.63; ORliver iron: 1.34, 95% CI: 1.07, 1.68). Ferritin partially mediated the association between FI and liver steatosis (proportion mediated: 7%, 95% CI: 2-12%).

Our study provides credible evidence on the causal role of T2D and elevated insulin in liver steatosis and cirrhosis risk and indicates ferritin may play a mediating role in this association.

Nonalcoholic steatohepatitis (NASH) represents a severe disease subtype of nonalcoholic fatty liver disease (NAFLD) that is thought to be highly associated with systemic metabolic abnormalities. It is characterized by a series of substantial liver damage, including hepatocellular steatosis, inflammation, and fibrosis. The end stage of NASH, in some cases, may result in cirrhosis and hepatocellular carcinoma (HCC). Nowadays a large number of investigations are actively under way to test various therapeutic strategies, including emerging oligonucleotide drugs (e.g., antisense oligonucleotide, small interfering RNA, microRNA, mimic/inhibitor RNA, and small activating RNA) that have shown high potential in treating this fatal liver disease. This article systematically reviews the pathogenesis of NASH/NAFLD, the promising druggable targets proven by current studies in chemical compounds or biological drug development, and the feasibility and limitations of oligonucleotide-based therapeutic approaches under clinical or pre-clinical studies.

It is known that gestational diabetes mellitus (GDM)-complicated pregnancies could affect maternal cardiometabolic health after delivery, resulting in hepatic dysfunction and a heightened risk of developing non-alcoholic fatty liver disease (NAFLD). Hence, this study aims to summarise existing literature on the impact of GDM on NAFLD in mothers and investigate the intergenerational impact on NAFLD in offspring.

Using 4 databases (PubMed, Embase, Web of Science and Scopus) between January 1980 and December 2023, randomized controlled trials and observational studies that assessed the effect of maternal GDM on intergenerational liver outcomes were extracted and analysed using random-effects meta-analysis to investigate the effect of GDM on NAFLD in mothers and offspring. Pooled odds ratio (OR) was calculated using hazards ratio (HR), relative risk (RR), or OR reported from each study, with corresponding 95% confidence intervals (CI), and statistical heterogeneity was assessed with the Cochran Q-test and I2 statistic, with two-sided p values. The study protocol was pre-registered on PROSPERO (CRD42023392428).

Twenty studies pertaining to mothers and offspring met the inclusion criteria and 12 papers were included further for meta-analysis on intergenerational NAFLD development. Compared with mothers without a history of GDM, mothers with a history of GDM had a 50% increased risk of developing NAFLD (OR 1.50; 95% CI: 1.21-1.87, over a follow-up period of 16 months-25 years. Similarly, compared with offspring born to non-GDM-complicated pregnancies, offspring born to GDM-complicated pregnancies displayed an approximately two-fold elevated risk of NAFLD development (2.14; 1.57-2.92), over a follow-up period of 1-17.8 years.

This systematic review and meta-analysis suggests that both mothers and offspring from GDM-complicated pregnancies exhibit a greater risk to develop NAFLD. These findings underline the importance of early monitoring of liver function and prompt intervention of NAFLD in both generations from GDM-complicated pregnancies.

No funding was available for this research.

Metabolic-associated fatty liver disease (MAFLD) has been identified as risk factor of incident type 2 diabetes (T2D), but the underlying postprandial mechanisms remain unclear. We compared the glucose metabolism, insulin resistance, insulin secretion, and insulin clearance post-oral glucose tolerance test (OGTT) between individuals with and without MAFLD. We included 50 individuals with a body mass index (BMI) between 25 and 40 kg/m2 and ≥1 metabolic alteration: increased fasting triglycerides or insulin, plasma glucose 5.5-6.9 mmol/L, or glycated hemoglobin 5.7-5.9%. Participants were grouped according to MAFLD status, defined as hepatic fat fraction (HFF) ≥5% on MRI. We used oral minimal model on a frequently sampled 3 h 75 g-OGTT to estimate insulin sensitivity, insulin secretion, and pancreatic β-cell function. Fifty percent of participants had MAFLD. Median age (IQR) [57 (45-65) vs. 57 (44-63) yr] and sex (60% vs. 56% female) were comparable between groups. Post-OGTT glucose concentrations did not differ between groups, whereas post-OGTT insulin concentrations were higher in the MAFLD group (P < 0.03). Individuals with MAFLD exhibited lower insulin clearance, insulin sensitivity, and first-phase pancreatic β-cell function. In all individuals, increased insulin incremental area under the curve and decreased insulin clearance were associated with HFF after adjusting for age, sex, and BMI (P < 0.02). Among individuals with metabolic alterations, the presence of MAFLD was characterized mainly by post-OGTT hyperinsulinemia and reduced insulin clearance while exhibiting lower first phase β-cell function and insulin sensitivity. This suggests that MAFLD is linked with impaired insulin metabolism that may precede T2D.NEW & NOTEWORTHY Using an oral glucose tolerance test, we found hyperinsulinemia, lower insulin sensitivity, lower insulin clearance, and lower first-phase pancreatic β-cell function in individuals with MAFLD. This may explain part of the increased risk of incident type 2 diabetes in this population. These data also highlight implications of hyperinsulinemia and impaired insulin clearance in the progression of MAFLD to type 2 diabetes.

Metabolic associated fatty liver disease (MAFLD) is a prevalent chronic liver condition globally, currently lacking universally recognized therapeutic drugs, thereby increasing the risk of cirrhosis and hepatocellular carcinoma. Research has reported an association between white adipose tissue and MAFLD.

White adipose tissue (WAT) is involved in lipid metabolism and can contribute to the progression of MAFLD by mediating insulin resistance, inflammation, exosomes, autophagy, and other processes. This review aims to elucidate the mechanisms through which WAT plays a role in the development of MAFLD.

WAT participates in the occurrence and progression of MAFLD by mediating insulin resistance, inflammation, autophagy, and exosome secretion. Fibrosis and restricted expansion of adipose tissue can lead to the release of more free fatty acids (FFA), exacerbating the progression of MAFLD. WAT-secreted TNF-α and IL-1β, through the promotion of JNK/JKK/p38MAPK expression, interfere with insulin receptor serine and tyrosine phosphorylation, worsening insulin resistance. Adiponectin, by inhibiting the TLR-4-NF-κB pathway and suppressing M2 to M1 transformation, further inhibits the secretion of IL-6, IL-1β, and TNF-α, improving insulin resistance in MAFLD patients. Various gene expressions within WAT, such as MBPAT7, Nrf2, and Ube4A, can ameliorate insulin resistance in MAFLD patients. Autophagy-related gene Atg7 promotes the expression of fibrosis-related genes, worsening MAFLD. Non-pharmacological treatments, including diabetes-related medications and exercise, can improve MAFLD.

The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a term that entails a broad spectrum of conditions that vary in severity. Its development is influenced by multiple factors such as environment, microbiome, comorbidities, and genetic factors. MASLD is closely related to metabolic syndrome as it is caused by an alteration in the metabolism of fatty acids due to the accumulation of lipids because of an imbalance between its absorption and elimination in the liver. Its progression to fibrosis is due to a constant flow of fatty acids through the mitochondria and the inability of the liver to slow down this metabolic load, which generates oxidative stress and lipid peroxidation, triggering cell death. The development and progression of MASLD are closely related to unhealthy lifestyle habits, and nutritional epigenetic and genetic mechanisms have also been implicated. Currently, lifestyle modification is the first-line treatment for MASLD and nonalcoholic steatohepatitis; weight loss of ≥10% produces resolution of steatohepatitis and fibrosis regression. In many patients, body weight reduction cannot be achieved; therefore, pharmacological treatment should be offered in particular populations.

The diagnosis and comprehension of nonalcoholic fatty liver disease (NAFLD), recently redefined as metabolic dysfunction-associated steatotic liver disease (MASLD) are gaining a better understanding. In this study, we examined the association between visceral fat area and skeletal muscle mass ratio (VSR) and the prevalence of MASLD in a Chinese population.

A cross-sectional study was conducted involving 10,916 individuals who underwent bioelectrical impedance analysis, along with anthropometric and biochemical measurements, from January 2022 to June 2023. According to the VSR distribution, sex-specific quartiles of VSR within the study population were defined. Linear trend tests were performed for the categorized VSR variables. Logistic regression models were performed to estimate the odds ratio and 95% confidence intervals between VSR distribution and MASLD prevalence stratified by sex.

The prevalence of MASLD was 37.94% in the overall population (56.34% male), and it gradually increased with higher VSR levels in both genders (P < 0.001). Logistic regression analysis demonstrated a significant association between VSR and MASLD prevalence after adjusting for confounders. The odds ratio (95% confidence interval) for MASLD, comparing the lowest to the highest VSR quartile, was 3.159 (2.671, 3.736) for men and 2.230 (1.764, 2.819) for women (all P < 0.001). Restricted cubic splines also indicated significant non-linear relationships between VSR and MASLD prevalence.

VSR is positively associated with the prevalence of MASLD in this Chinese population, with a notably higher risk for men as VSR increases compared to women.

The novel term Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is proposed to replace non-alcoholic fatty liver disease (NAFLD) to highlight the close association with the metabolic syndrome. MASLD encompasses patients with liver steatosis and at least one of five cardiometabolic risk factors which implies that these patients are at increased risk of cardiovascular disease (CVD). Indeed, the prevalence of CVD in MASLD patients is increased and CVD is recognized as the most common cause of death in MASLD patients. We here present an update on the pathophysiology of CVD in MASLD, discuss the risk factors, and suggest screening for CVD in patients with MASLD. Currently, there is no FDA-approved pharmacological treatment for MASLD, and no specific treatment recommended for CVD in patients with MASLD. Thus, the treatment strategy is based on weight loss and a reduction and treatment of CVD risk factors. We recommend screening of MASLD patients for CVD using the SCORE2 system with guidance to specific treatment algorithms. In all patients with CVD risk factors, lifestyle intervention to induce weight loss through diet and exercise is recommended. Especially a Mediterranean diet may improve hyperlipidemia and if further treatment is needed, statins should be used as first-line treatment. Further, anti-hypertensive drugs should be used to treat hypertension. With the epidemic of obesity and type 2 diabetes mellitus (T2DM) the risk of MASLD and CVD is expected to increase, and preventive measures, screening, and effective treatments are highly needed to reduce morbidity and mortality in MASLD patients.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum β-hydroxybutyrate (β-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum β-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity (n = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum β-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower HMGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum β-HB correlated with liver mitochondrial β-hydroxyacyl-CoA dehydrogenase (β-HAD) activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum β-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD.NEW & NOTEWORTHY Serum β-hydroxybutyrate (β-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating β-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum β-HB. Our work supports serum β-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.

The pursuit of studying this subject is driven by the urgency to address the increasing global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) and its profound health implications. NAFLD represents a significant public health concern due to its association with metabolic disorders, cardiovascular complications, and the potential progression to more severe conditions like non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Liver estrogen signaling is important for maintaining liver function, and loss of estrogens increases the likelihood of NAFLD in postmenopausal women. Understanding the multifaceted mechanisms underlying NAFLD pathogenesis, its varied treatment strategies, and their effectiveness is crucial for devising comprehensive and targeted interventions. By unraveling the intricate interplay between genetics, lifestyle, hormonal regulation, and gut microbiota, we can unlock insights into risk stratification, early detection, and personalized therapeutic approaches. Furthermore, investigating the emerging pharmaceutical interventions and dietary modifications offers the potential to revolutionize disease management. This review reinforces the role of collaboration in refining NAFLD comprehension, unveiling novel therapeutic pathways, and ultimately improving patient outcomes for this intricate hepatic condition.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease across all age groups. Limited studies have been conducted to consider the relationship between NAFLD and liver size. This study aimed to compare the size of the liver between NAFLD patients and healthy controls.

This case-control study was conducted on NAFLD patients (n = 300), and healthy subjects (n = 300) referred to the Golestan Hospital of Ahvaz from April to August 2021. All individuals underwent ultrasonography examination, and liver size was measured in the midclavicular line. Fatty liver was divided into three grades, I (mild), II (moderate), and III (severe), according to the disease severity. Anthropometric parameters, including age, sex, weight, height, and body mass index (BMI), were recorded. Finally, the size of the liver and its relationship with NAFLD and anthropometric parameters was evaluated.

Patients had significantly higher weight, and BMI mean values than controls (P < 0.001). In comparison to controls, NAFLD patients had considerably larger livers on average. (149.05 ± 12.60 mm vs. 134.51 ± 12.09; P < 0.001). There was a significant tendency for larger liver size in normal to severe fatty liver patients (P < 0.001). In patients with mild, moderate, and severe NAFLD, the mean liver size was 144.34 ± 11.35, 154.21 ± 10.84, and 158.63 ± 13.45 mm, respectively. The mean liver size in both groups was significantly higher in males than females (P < 0.05). Age (P = 0.037), sex (P < 0.001), height (P < 0.001), BMI (P = 0.008), and steatosis (P < 0.001) were independent variables for predicting the liver size.

The liver size of persons with fatty liver was substantially more considerable than healthy people. The size of the liver was substantially linked with sex, age, BMI, fatty liver, and hepatic steatosis grade. A straightforward way to predict fatty liver is to use ultrasonography to determine the size of the liver.

Non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with cardiovascular-related mortality, leading to a higher mortality rate compared to the general population. However, few reports have examined cardiovascular events in non-obese MASLD mouse models. In this study we created a mouse model to mimic this condition. In this study involving seven-week-old C57BL/6J male mice, two dietary conditions were tested: a standard high-fat/high-cholesterol diet (STHD-01) and a combined diet of STHD-01 and ethanol. Over periods of 6 and 12 weeks, we analyzed the effects on liver and cardiac tissues using various staining techniques and PCR. Echocardiography and blood tests were also performed to assess cardiac function and liver damage. The results showed that mice on the ethanol-supplemented STHD-01 diet developed signs of steatohepatitis and cardiac dysfunction, along with increased sympathetic activity, as early as 6 weeks. At 12 weeks, more pronounced exacerbations accompanied with cardiac dilation, advanced liver fibrosis, and activated myocardial fibrosis with sympathetic activation were observed. This mouse model effectively replicated non-obese MASLD and cardiac dysfunction over a 12-week period using a combined diet of STHD-01 and ethanol. This dietary approach highlighted that both liver inflammation and fibrosis, as well as cardiac dysfunction, could be significantly worsened due to the activation of the sympathetic nervous system. Our results indicate that alcohol, even when completely metabolized on the day of drinking, exacerbates the progression of non-obese MASLD and cardiac dysfunction.

Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease. This paper briefly discusses the dysregulation in lipid metabolism during various stages of MASLD.

Metabolic-associated fatty liver disease (MAFLD) is an increasingly prevalent cause of chronic liver disease. In 2020, the FibroScan-AST (FAST) score was internationally validated as a new tool able to identify patients with steatohepatitis who benefit the most from further therapies, based on liver transient elastography (LTE) findings and serum levels of aspartate aminotransferase (AST). We aimed to identify, in MAFLD patients, which metabolic features may predict a higher FAST score.

Retrospective study of consecutive patients with MAFLD submitted to LTE for two consecutive years. Patients without an AST sample collected within 6 months of the LTE were excluded. FAST score was calculated, stratifying the patient's risk as low (<0.35), medium (0.35-0.67), or high (>0.67).

The sample included 117 patients, 53.0% of the female gender, with a mean age of 53 years. On multivariate analysis, patients with type 2 diabetes (T2DM) (p < 0.001), dyslipidemia (p = 0.046), and smoking habits (p = 0.037) presented with significantly higher FAST score values. Furthermore, diabetic patients did not only present significantly higher FAST scores but were also more frequently assigned to the high-risk group according to FAST score criteria (OR = 9.2; 95% CI = 1.8-45.5; p = 0.007).

Calculating the FAST score, patients with T2DM presented a significantly higher risk of having significant fibrosis and steatohepatitis. Physicians may rely on this validated instrument to more easily identify which patients with T2DM and MAFLD benefit the most from a specialized follow-up.

The liver is the leading site for lipid metabolism, involving not only fatty acid beta-oxidation but also de novo synthesis of endogenous triglycerides and ketogenesis. The liver maintains systemic lipid homeostasis by regulating lipid synthesis, catabolism, and transportation. Dysregulation of hepatic lipid metabolism precipitates disorders, such as non-alcoholic fatty liver disease (NAFLD), affecting the whole body. Thus, comprehending and studying hepatic lipid metabolism is crucial for preventing and treating metabolic liver diseases. Traditionally, researchers have investigated the impact of a single nutrient on hepatic lipid metabolism. However, real-life dietary patterns encompass diverse nutrients rather than single components. In recent years, there have been increased studies and notable progress regarding the effects of distinct dietary patterns on hepatic lipid metabolism. This review summarizes the influence of diverse dietary patterns on hepatic lipid metabolism, elucidating underlying molecular mechanisms and appraising the therapeutic potential of dietary patterns in managing hepatic steatosis.

Metabolic flexibility refers to the ability of tissues to adapt their use of energy sources according to substrate availability and energy demands. This review aims to disentangle the emerging mechanisms through which altered metabolic flexibility and insulin resistance promote NAFLD and heart disease progression. Insulin resistance and metabolic inflexibility are central drivers of hepatic and cardiac diseases in individuals with type 2 diabetes. Both play a critical role in the complex interaction between glucose and lipid metabolism. Disruption of metabolic flexibility results in hyperglycemia and abnormal lipid metabolism, leading to increased accumulation of fat in the liver, contributing to the development and progression of NAFLD. Similarly, insulin resistance affects cardiac glucose metabolism, leading to altered utilization of energy substrates and impaired cardiac function, and influence cardiac lipid metabolism, further exacerbating the progression of heart failure. Regular physical activity promotes metabolic flexibility by increasing energy expenditure and enabling efficient switching between different energy substrates. On the contrary, weight loss achieved through calorie restriction ameliorates insulin sensitivity without improving flexibility. Strategies that mimic the effects of physical exercise, such as pharmacological interventions or targeted lifestyle modifications, show promise in effectively treating both diabetes and NAFLD, finally reducing the risk of advanced liver disease.

The heritability of nonalcoholic fatty liver disease (NAFLD) in lean individuals is undetermined. This familial aggregation study aimed to evaluate familial linkage for NAFLD and the risk of NAFLD among first-degree relatives of probands with lean NAFLD.

This study prospectively recruited cohorts of probands with lean NAFLD, probands with obese NAFLD, and lean probands with non-NAFLD and their respective first-degree relatives. A total of 257 participants were evaluated for liver steatosis, defined by the controlled attenuation parameter ≥288 dB/m2 , metabolic characteristics, and the PNPLA3, TM6SF2, and MBOAT7 polymorphisms.

The prevalence of NAFLD in first-degree relatives of lean NAFLD probands (39.9%) was similar to that in the obese NAFLD group (36.9%) and was significantly higher than in lean persons without NAFLD (19.1%). First-degree relatives of probands with NAFLD who were male, and had central obesity, hypertriglyceridaemia, insulin resistance, and the PNPLA3 rs738409C>G allele had a significantly higher prevalence of NAFLD. After multivariable adjustment for gender, metabolic characteristics, and the PNPLA3 rs738409C>G allele, first-degree relatives of probands with lean NAFLD (odds ratio [OR], 5.13; 95% CI, 1.77-14.86) and obese NAFLD (OR, 3.20; 95% CI, 1.14-8.99) exhibited an increased risk of NAFLD compared with those of lean controls without NAFLD.

Our well-phenotype cohorts revealed familial clustering of NAFLD and higher risks of NAFLD in first-degree relatives of probands with lean or obese NAFLD. The findings encourage clinicians caring for NAFLD patients to be more vigilant for NAFLD in their family members.