Search Results (1,884)

As the rates of type 2 diabetes and obesity have increased globally, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic steatotic fatty liver disease (NAFLD), has risen concomitantly worldwide. MASLD is now the most common etiology of chronic liver disease and is the leading indication for liver transplantation in the United States. Patients with MASLD have an increased risk of progression to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, hepatocellular carcinoma, extrahepatic malignancies, as well as liver- and cardiovascular-related mortality. Diet and lifestyle modifications with a goal of ≥10% total body weight loss—required to reverse steatosis, steatohepatitis, and fibrosis—are often challenging and ineffective. Although novel pharmacotherapies have recently been approved and others are in development, cost, adherence, and adverse effects remain potential limitations. Bariatric surgery, including Roux-en-Y gastric bypass and sleeve gastrectomy, is highly efficacious and a cost-effective treatment for obesity and associated medical problems. However, bariatric surgery may be associated with morbidity and mortality. Endoscopic bariatric and metabolic therapy (EBMT) has recently emerged as a promising treatment modality and offers an alternative to surgery. Primary EBMTs include intragastric balloon placement, aspiration therapy, endoscopic sleeve gastroplasty, duodenal mucosal resurfacing, duodenal–jejunal bypass liner, and primary obesity surgery endoluminal (POSE 2.0). Secondary EBMTs include transoral outlet reduction, argon plasma coagulation of the anastomosis, and revisional endoscopic sleeve procedure. We review the recent literature on primary EBMTs and secondary EBMTs for the treatment of obesity and MASLD, the pathophysiologic mechanisms, efficacy, safety, and patient outcomes in MASLD in this narrative review. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by hepatic steatosis in individuals with at least one cardiometabolic risk factor, most commonly type 2 diabetes mellitus (T2DM). People with non-alcoholic fatty liver disease, even without other metabolic factors, have a higher risk of T2DM. MASLD includes isolated liver steatosis, metabolic dysfunction-associated steatohepatitis, fibrosis, cirrhosis, and MASH-related hepatocellular carcinoma. MASLD patients are also at a higher risk of developing T2DM than the general population. International guidelines recommend a stepwise approach for identifying those at high risk of fibrotic progression, using the FIB-4 index for initial screening, followed by transient elastography. The link between MASLD and T2DM is notable due to shared pathophysiological mechanisms, some of which are reversible with treatment used in T2DM. Many new glucose-lowering drugs have also proven effective in improving anthropometric and metabolic parameters, as well as the stage of hepatic steatosis and fibrosis. Recent evidence suggests that GLP-1RAs and SGLT2is have beneficial effects in MASLD patients with T2DM. Specifically, GLP-1RAs improve hepatic insulin signaling, modulate lipid metabolism, reduce inflammation, and decrease hepatocyte oxidative stress. European guidelines recommend resmetirom as a MASH-targeted therapy, if locally approved, for adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥ 2) and GLP-1RAs in MASH, including compensated cirrhosis, but they should be used for their respective indications, such as T2DM and obesity. Given the post-COVID burden of MASLD and its high risk of liver fibrosis progression among T2DM patients, this review specifically provides an overview of the complex relationship between MASLD and T2DM. Additionally, it examines current understanding of liver fibrosis evaluation and the effects of novel treatment options, with a particular focus on glucose-lowering therapies and their effects on necroinflammation, hepatic fat accumulation, and fibrosis progression in patients with MASLD and T2DM. Full article

Objectives: The study explores the comparative effects of atorvastatin (ATV), policosanol (PCO), and their combination (ATV+PCO) on metabolic stress and associated organ damage in hyperlipidemic–hyperglycemic zebrafish. Methodology: Hyperlipidemic–hyperglycemic zebrafish (n = 112) were segregated into four groups (n = 28/group) and fed either with a high-cholesterol (HC, 4% w/w) and a high-galactose (HG, 30% w/w) diet, HCHG diet with policosanol (PCO, 0.1% w/w), atorvastatin (ATV, 0.1% w/w), or ATV+PCO (0.1% w/w each). After 12 weeks of supplementation, survivability and embryo production were assessed, along with biochemical and histological examinations of various organs across the groups. Results: Following a 12-week dietary regime, compromised zebrafish survival probability (0.75) was observed in the ATV group, compared to the PCO group (0.89), which increased to 0.82 with combined intake of ATV+PCO. A significantly greater effect of ATV than PCO was observed in reducing the HCHG elevated TC, TG, and LDL-C levels. However, compared to the ATV, a significantly higher HDL-C/TC (%) ratio was spotted in the PCO. Unlike individual supplementation (ATV or PCO), a combined intake (ATV+PCO) proved highly effective in counteracting dyslipidemia, especially by augmenting the HDL-C/TC (%) ratio. Interestingly, no protective effect of ATV was observed against elevated blood glucose levels, oxidative stress, or diminished antioxidant markers. Whereas ATV, in combination with PCO, significantly reduced blood glucose and MDA levels and elevated sulfhydryl content and antioxidant variables (ferric iron reduction ability and paraoxonase activity). ATV+PCO supplementation effectively mitigated HCHG-induced fatty liver, inflammation, ROS generation in the kidney, and brain senescence. Likewise, ATV+PCO improved reproductive health, elevating spermatozoa counts and embryo production ability of zebrafish. Notably, ATV+PCO supplementation significantly inhibited the HCHG-induced eye damage and demyelination in the retina, while ATV alone failed to establish any such changes. Conclusions: The study indicates the combinational therapy of ATV+PCO may offer a possible treatment to counter the metabolic stress and associated events in hyperlipidemic–hyperglycemic zebrafish. Full article

Background/Objectives: Metabolic-dysfunction-associated fatty liver disease (MASLD) is characterised by an excessive hepatic lipid accumulation. The present research aims to study the impact of an Opuntia stricta var. dillenii peel extract and an Opuntia ficus-indica var. colorada pulp extract, known for their high content of betalains and phenolic compounds, on the prevention of hepatic lipid accumulation in the liver of rats with steatosis. Methods: For this, MASLD was induced in 60 male Wistar rats by a high-fat high-fructose diet. They were supplemented with Opuntia stricta var. dillenii peel extract or Opuntia ficus-indica var. colorada pulp extract at 25 or 100 mg/kg body weight/d. Results: The high-fat high-fructose diet caused an increase in final body and liver weight, hepatic triglyceride (TG) content, and altered liver histology. The increase in hepatic TG was due to the rise in fatty acid uptake and the increased assembly of TG, although increased de novo lipogenesis cannot be ruled out. The treatment with a low dose of Opuntia ficus-indica var. colorada pulp extract (L-OFI group) significantly prevented hepatic TG accumulation, and the high dose (H-OFI group) showed a tendency towards lower values compared to the rats fed the high-fat high-fructose diet. The main mechanism of action appears to be a down-regulation of fatty acid uptake. By contrast, Opuntia stricta var. dillenii peel extract did not prevent the high-fat high-fructose diet-induced steatosis. Conclusions: Overall, Opuntia ficus-indica var. colorada pulp extract may represent a potential strategy for MASLD prevention, although its beneficial effects require confirmation in human studies. Full article

Background/Objectives: This study evaluated whether yoghurt containing Apilactobacillus kunkeei DSM 12361 protects rats against non-alcoholic fatty liver disease (NAFLD). We hypothesized that this fructophilic probiotic, with anti-inflammatory properties, may affect NAFLD progression by improving the gut microbiome, lowering intestinal ethanol production, and modulating inflammatory and metabolic pathways linked to hepatic fat accumulation. Methods: Wister rats were randomized into three groups; rats in the control group (HFrD) were fed a high-fructose (70%) diet while rats in experimental groups were fed the same diet mixed with 10% of yoghurt containing YC-180 starter culture (HFrD-Y) or yoghurt containing YC-180 and Apilactobacillus kunkeei DSM 12361 (HFrD-Y-A). Results: After six weeks of intervention, levels of plasma triglycerides, cholesterol, glucose, liver enzymes (ALT and AST), interleukin (IL)-6, fecal ethanol, Enterobacteriaceae, and hepatic index were significantly increased (p < 0.05) in the HFrD group as compared to rats in both experimental groups. Moreover, plasma levels of liver enzymes, lipid profile, glucose, and IL-6 were significantly lower (p < 0.05) in rats of the HFrD-Y-A group than those in the HFrD-Y group. Furthermore, plasma levels of IL-10 and fecal Lactobacilli and Bifidobacteria were significantly increased (p < 0.05) in the experimental groups when compared to rats in the control group. Conclusions: In sum, the obtained results indicated that yoghurt containing Apilactobacillus kunkeei could decrease the risk of non-alcoholic fatty liver disease (NAFLD) through (a) blocking the inflammation process associated with NAFLD, (b) enhancing the lipid profile, (c) lowering fecal ethanol, and (III) decreasing the levels of fecal Enterobacteriaceae in comparison with levels of fecal Lactobacilli and Bifidobacteria in rats. More research on molecular mechanisms of the potential effects of the Apilactobacillus kunkeei strain against NAFLD is still required. Full article

Background: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disorder associated with impaired lipid metabolism and oxidative stress. As a natural antioxidant and dithiol compound, α-lipoic acid (ALA) may play a beneficial role in modulating hepatic metabolism. This study investigates the potential mechanisms through which ALA may alleviate NAFLD. Methods: To construct an NAFLD model, NCTC 1469 cells were exposed to oleic acid and palmitic acid (OA/PA) and glucose for 24 h. RT-qPCR, Western blotting, and siRNA analyses were used to examine the effects and mechanisms of ALA. In vivo, C57BL/6J mice were fed a high-fat diet for 11 weeks and treated with ALA (200 mg/kg/day, intragastrical) for 4 weeks to evaluate its impact on NAFLD. Results: In NCTC 1469 cells exposed to OA/PA and glucose, ALA markedly reduced lipid accumulation by activating TFEB, which in turn promoted fatty acid β-oxidation and chaperone-mediated autophagy (CMA). Furthermore, ALA activated NRF2-dependent CMA and mitigated oxidative stress. Inhibition of AMPK or silencing of TFEB/NRF2 abolished these effects, indicating the key role of the AMPK–TFEB/NRF2 axis. In HFD-fed mice, ALA alleviated hepatic steatosis, serum lipid abnormalities, and liver injury, consistent with its activation of CMA and β-oxidation and reduction in oxidative stress via this pathway. Conclusions: ALA synchronously activates CMA, β-oxidation, and antioxidant responses via a unified AMPK pathway to reduce lipid accumulation and oxidative stress, providing a mechanistically integrated therapeutic strategy for NAFLD. Full article

The triad association among type 2 diabetes mellitus (T2DM), metabolic associated fatty liver disease (MAFLD), and incretin secretion dysfunction, including GLP-1 (glucagon-like peptide-1) secretion dysfunction, maintains a critical cardiovascular risk and liver-related mortality. The aim of this study is to establish interactions between the GLP-1 plasma levels and metabolic syndrome clusters and adipokines profile (leptin, adiponectin, resistin) and proinflammatory cytokines (TNFα, IL-6, IL1β, IL-17) in diabetic subjects with or without MAFLD. The data revealed that insulin resistance (HOMA-IR) is present in all groups. MAFLD is more common in men than in women. The average FLI score in group IV was ≥70, confirming the diagnosis of MAFLD. The disorder of GLP-1 secretion is more pronounced in women than in men. HOMA-IR is negatively associated with plasma GLP-1 depletion in the MAFLD, T2DM, and MAFLD + T2DM groups. Adiponectin levels are decreased in all groups, as for GLP-1. In contrast, leptin, resistin, TNFα, IL-6, IL-1β, and IL-17 levels show an inverse correlation with GLP-1. GLP-1 accurately reflects metabolic and inflammatory status in subjects with MAFLD, T2DM, and diabetes—steatosis. The applied multivariate linear regression model confirms a highly significant association between MAFLD and GLP-1. It appears that plasma GLP-1 can be considered as biomarker in MAFLD and T2DM related to sex-gender disparities. Longitudinal studies are required to confirm these data. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common liver disease and is characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and inflammation play important roles in hepatic lipid accumulation. Although CILP2 has been implicated in lipid metabolism, its role in MASLD remains unclear. Hepatic steatosis was induced in mice by a high-fat diet in this study. CILP2 was overexpressed in mouse livers and in vitro hepatocytes using the Ad-CILP2 adenovirus. CILP2 KO mice were also used in the experiments. Liver tissues and hepatocytes were collected for further analysis. CILP2 expression was upregulated in steatotic liver tissue and hepatocytes. CILP2 overexpression upregulated genes related to fatty acid synthesis (Srebp-1c, Fasn, Acc, Scd1, and Cd36), promoted lipid accumulation, and elevated the expression of proinflammatory cytokines (Il6, Tnf, and Il1b). Conversely, CILP2 knockout reduced high-fat diet-induced hepatic steatosis and improved glucose metabolism. Mechanistically, CILP2 activated the IRE1α/XBP1 branch of the ER stress pathway, thereby promoting lipid synthesis and inflammation, effects that were partially alleviated by 4-PBA and STF-083010 treatments. Our findings indicate that CILP2 contributes to hepatic lipid accumulation and inflammation via the IRE1α/XBP1 pathway and may represent a potential therapeutic target for MASLD intervention. Full article

Metabolic associated fatty liver disease (MAFLD), redefined from non-alcoholic fatty liver disease (NAFLD), is a global health concern driving the search for dietary interventions based on natural compounds. Phloroglucinaldehyde (PGA), a primary phenolic metabolite of the widely consumed anthocyanin cyanidin-3-glucoside (C3G) found in berries and other fruits, has emerged as a promising candidate due to its potential higher bioavailability than its parent compound. This study investigates the protective effects of PGA against high-fat diet (HFD)-induced MAFLD. Using both in vitro (LO2 cells) and in vivo (C57BL/6J mice) models, we found that PGA administration significantly attenuated body weight gain and hepatic steatosis, while reducing serum levels of TG, TC, liver transaminases (AST & ALT), and insulin resistance (p < 0.05). Further liver lipidomic profiling revealed that PGA supplementation specifically down-regulated 46 lipid species (p < 0.05), predominantly triglycerides characterized by long-chain and very-long-chain saturated fatty acids. Mechanistically, PGA enhanced the hepatic antioxidant capacity by increasing superoxide dismutase (SOD) activity (p < 0.05) and decreasing malondialdehyde (MDA) (p < 0.05) and exerted anti-inflammatory effects by reducing pro-inflammatory cytokines (IL-6, TNF, MCP-1) (p < 0.05) and endotoxin levels (p < 0.05). Correlation analyses further linked the down-regulated lipids to improvements in oxidative stress and inflammation. Our findings underscore that PGA, a key bioactive metabolite derived from dietary anthocyanins, alleviates MAFLD through its potent antioxidant and anti-inflammatory properties, highlighting its potential as a functional food ingredient or nutraceutical for metabolic health. Full article

Background/Objectives: Nutraceuticals, including short-chain fatty acids (SCFAs) and antioxidants (AOXs), are nutrient-derived bioactive compounds considered as potential treatments for metabolic-associated steatotic liver disease (MASLD). However, in vitro studies of their effects are limited by inconsistent experimental conditions, including differences in cell lines, methods of steatosis induction, and culture media, and by reliance on qualitative rather than quantitative assessments. Here, we systematically evaluate the anti-steatotic potential of eight commonly used nutraceuticals—three SCFAs (butyrate, acetate, and propionate) and five AOXs (resveratrol, curcumin, berberine, chlorogenic acid, and vitamin E)—using a standardized in vitro approach. Methods: Following a systematic literature review to identify common experimental conditions, we developed an assay to validate steatosis induction and quantified the effects of the nutraceuticals. For our studies we used the HepG2 liver cancer cell line and the Fa2N-4 immortalized hepatocyte cell line. Steatosis was modeled by stimulating cells with free fatty acids and fructose for 48 h. Nutraceuticals were added either concurrently with steatotic stimulation, to assess preventive effects, or after 24 h to assess therapeutic effects. Anti-steatotic drugs (resmetirom, semaglutide, obeticholic acid, and a DGAT2 inhibitor) were included as positive controls. Intracellular triglyceride levels were measured to quantify steatosis. Results: A systematic review of 46 studies revealed large differences in culture conditions, steatosis induction, and nutraceutical assessment. In our experiments, most nutraceuticals did not reduce intracellular triglycerides, with the exception of vitamin E. Surprisingly, butyrate, berberine, and curcumin increased triglyceride accumulation. Resmetirom was the only drug that significantly decreased triglycerides, while obeticholic acid, semaglutide, and the DGAT2 inhibitor showed minimal or inconsistent effects. Fa2N-4 cells were generally more sensitive than HepG2 cells, showing larger absolute changes in triglyceride levels in response to both nutraceuticals and resmetirom. Conclusions: We established a standardized in vitro assay to evaluate the anti-steatotic potential of nutraceuticals. Using this system, we found that SCFAs and AOXs did not consistently reduce intracellular triglycerides, highlighting the need for quantitative assessments and careful validation when studying anti-steatotic interventions in vitro. Full article

The increasing prevalence of metabolic dysfunction-associated fatty liver disease (MASLD) in children requires robust, non-invasive biomarkers to enable accurate disease staging and risk stratification. Elevated serum levels of homocysteine (Hcy) have emerged as potential risk factors for cardiometabolic disease in adults, including MASLD. In this observational retrospective study, we investigated the role of serum Hcy levels as a potential biomarker for disease severity and liver fibrosis in a pediatric cohort of 182 children with MASLD. In 89 patients, liver biopsy allowed the classification into metabolic dysfunction-associated steatohepatitis (MASH). Associations between Hcy, metabolic parameters, fibrosis scores, and histological features were examined, and the diagnostic performance of Hcy for liver fibrosis was evaluated using ROC analysis. Multivariate analyses identified elevated Hcy levels as independently associated with HOMA-IR (β = 0.55; p = 0.049), TG/HDL ratio (β = 3.23; p = 0.002), and liver fibrosis (β = 2.59; p = 0.04). Hcy showed a predictive accuracy of 81% for fibrosis. However, the combined diagnostic models of Hcy with non-invasive fibrotic scores (i.e., APRI and FIB-4) or TG/HDL ratio showed only a modest accuracy (AUC = 0.62–0.69). In conclusion, our data suggest that Hcy is associated with fibrosis and cardiometabolic risk. However, these results should be interpreted as exploratory and do not establish homocysteine as a diagnostic biomarker. Full article

Background: Childhood obesity represents the most common nutritional and metabolic disorder in industrialized countries and constitutes a major public health concern. In Italy, 20–25% of school-aged children are overweight and 10–14% are obese, with marked regional variability. Excess adiposity in childhood is frequently associated with hypertension, dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease (NAFLD), predisposing to future cardiovascular disease (CVD). Objective: To investigate anthropometric indicators of cardiometabolic risk in 810 children and adolescents aged 7–17 years who underwent assessment for competitive sports eligibility at the Sports Medicine Unit of Modena, evaluate baseline knowledge of cardiovascular health aligned with ESC, AAP (2023), and EASO guidelines. Methods: 810 children and adolescents aged 7–17 years undergoing competitive sports eligibility assessment at the Sports Medicine Unit of Modena underwent evaluation of BMI percentile, waist circumference (WC), waist-to-height ratio (WHtR), and blood pressure. Cardiovascular knowledge and lifestyle habits were assessed via a previously used questionnaire. Anthropometric parameters, blood pressure (BP), and lifestyle-related knowledge and behaviors were assessed using standardized procedures. Overweight and obesity were defined according to WHO BMI-for-age percentiles. Elevated BP was classified based on the 2017 American Academy of Pediatrics age-, sex-, and height-specific percentiles. Statistical analyses included descriptive statistics, group comparisons, chi-square tests with effect size estimation, correlation analyses, and multivariable logistic regression models. Results: Overall, 22% of participants were overweight and 14% obese. WHtR > 0.5 was observed in 28% of the sample and was more frequent among overweight/obese children (p < 0.001). Elevated BP was detected in 12% of participants with available measurements (n = 769) and was significantly associated with excess adiposity (χ² = 7.21, p < 0.01; Cramér’s V = 0.27). In multivariable logistic regression analyses adjusted for age and sex, WHtR > 0.5 (OR 2.14, 95% CI 1.32–3.47, p = 0.002) and higher sedentary time (OR 1.41 per additional daily hour, 95% CI 1.10–1.82, p = 0.006) were independently associated with elevated BP, whereas BMI percentile lost significance when WHtR was included in the model. Lifestyle knowledge scores were significantly lower among overweight and obese participants compared with normal-weight peers (p < 0.01). Conclusions: WHtR is a sensitive early marker of cardiometabolic risk, often identifying at-risk children missed by BMI alone. Baseline cardiovascular knowledge was suboptimal. The observed gaps in cardiovascular knowledge underscore the importance of integrating anthropometric screening with structured educational interventions to promote healthy lifestyles and long-term cardiovascular prevention. Full article

Background: Consumption of fruits of different origins with specific (poly)phenolic profiles can modulate the gene expression of enzymes and the levels of metabolites in a photoperiod-dependent manner. However, there is little information on how this affects the profile of hepatic and muscular fatty acids (FAs) and how it interferes with metabolic pathways. This study aimed to determine whether consuming local or non-local cherries alters liver and muscle FA profiles under different photoperiods, and to identify the associated changes in metabolic gene expression and serum metabolites. Methods: Seventy-two Fischer 344 rats, fed a standard diet and either vehicle (VH), Local Cherry (LC), or non-Local Cherry (nLC), were exposed to different hours of light to simulate photoperiods (winter, spring/autumn, or summer) for 7 weeks. The FA profiles of the liver and muscle were determined using GC-FID, and the gene expression of key enzymes involved in FA metabolism was evaluated. Moreover, the composition of hydrophilic and lipophilic metabolites in the serum and liver was analyzed using nuclear magnetic resonance (NMR), and pathway analysis was performed. Results: Consumption of cherries in season (18 h of light) decreased saturated FAs levels in the liver, mainly palmitate, compared to their respective VH; interestingly, this effect was not observed in other photoperiods. Furthermore, muscle polyunsaturated FA (PUFAs) decreased, possibly due to increased oxidation. Conclusions: Seasonal cherry consumption improves the hepatic lipid profile and increases muscular oxidation. Future studies are needed to better define these effects and uncover the differences in lipid metabolism in response to cherry consumption. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is now recognized as the leading cause of chronic liver disease worldwide. MASLD spans a spectrum ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and is linked to progressive fibrosis and ultimately hepatocellular carcinoma (HCC). Growing evidence implicates cellular senescence (CS) and lipid droplets (LDs) as key drivers of disease progression, although their interaction remains poorly characterized. This review provides an integrative and stage-dependent synthesis of current mechanistic insights into how bidirectional crosstalk between CS and LD regulation shapes the transition from steatosis to MASH. Senescent hepatocytes display altered lipid metabolism, including upregulation of receptors such as cluster of differentiation (CD) 36, enhancing lipid uptake to meet increased energy demands. Initially, elevated free fatty acid influx can activate peroxisome-proliferator-activated receptor alpha (PPARα), promoting fatty acid oxidation (FAO) as a compensatory response. Over time, persistent CS under steatotic conditions leads to mitochondrial dysfunction and suppression of fatty acid oxidation (FAO), while the senescence-associated secretory phenotype (SASP), largely driven by nuclear factor—kappa B (NF-κB) signaling, promotes chronic hepatic inflammation. By framing LDs as active modulators of senescence-associated signaling rather than passive lipid stores, this review highlights how disruption of senescence–lipid feedback loops may represent a disease-modifying opportunity in MASLD progression. Full article

The liver plays a central role in numerous physiological processes, with one of its most critical functions being the regulation of lipid homeostasis through both the biogenesis and secretion of very low-density lipoproteins (VLDLs) and fatty acid oxidation. By forming and secreting VLDLs, the liver mitigates the influx of potentially toxic free fatty acids from the bloodstream and repurposes them for energy utilization throughout the body. Fatty acid oxidation is equally essential for maintaining hepatic lipid balance, and its disruption can lead to lipid accumulation and metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD). Even subtle alterations in these processes can have profound health consequences, contributing to chronic liver diseases and atherosclerosis—the leading cause of cardiovascular morbidity and mortality worldwide. Despite their importance, many aspects of hepatic VLDL formation, secretion, and fatty acid oxidation remain poorly understood. This narrative review highlights the pivotal role of the liver in maintaining lipid balance, summarizes current knowledge on fatty acid uptake and processing, provides an in-depth analysis of VLDL biogenesis and secretion, and underscores the need for continued research in this critical area of human health. Full article