Search Results (1,080)

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in the world. The disease progresses from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The modern concept of “multiple parallel hits” interprets disease progression as the result of the synergistic action of lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, proinflammatory signals, and gut–liver axis dysfunction. Against the background of the limited translation of preclinical data from animal models due to interspecies differences, the importance of human-oriented in vitro platforms compatible with controlled design and high-throughput screening is increasing. The current review analyzes MASLD models based on the HepG2 cell line, systematizing steatosis induction protocols, evaluating the metabolic characteristics and limitations of this cell, and comparing 2D monocultures, 3D systems, and co-cultures. HepG2 has been shown to demonstrate a predictable steatogenic response to free fatty acids (FFAs) and is convenient for reproducing early stages of pathogenesis and primary pharmacological selection of compounds. At the same time, key limitations of the model are highlighted, namely tumor origin, glycolytic shift (Warburg effect), reduced β-oxidation, impaired very-low-density lipoprotein (VLDL) assembly and secretion, and sharply reduced cytochrome P450 (CYP450) activity, as well as limited reproducibility of fructose-induced de novo lipogenesis (DNL). Comparative analysis demonstrates an increase in physiological relevance with the transition from 2D to 3D and multicomponent co-cultures, accompanied by increased complexity and cost, but allowing for the modeling of inflammation and fibrogenesis. The review justifies approaches to selecting the appropriate platform based on the specific research task. Full article

Milk fat synthesis in dairy cows is a complex process affected by ruminal fermentation, systemic metabolism, and mammary gland activity. To explore the metabolic interplay across these systems, a multi-tissue metabolomics approach (rumen fluid, plasma, and milk) using ultra-high-performance liquid chromatography–mass spectrometry was used to identify metabolic differences between Chinese Holstein cows with high (H-MF, 5.82 ± 0.41%) and low (L-MF, 3.60 ± 0.12%) milk fat content under the same diet. The bovine mammary epithelial cells (BMECs) were also cultured to evaluate the impact of a key metabolite, malic acid (MA), on lipid metabolism. Our findings reveal distinct metabolic profiles across rumen fluid, plasma, and milk, with 96, 109, and 79 differential metabolites, respectively, between the L-MF and H-MF groups. In rumen fluid, H-MF cows showed higher levels of lauric acid and succinic acid, linked to fatty acid biosynthesis, while the L-MF cows had elevated citraconic and orotic acids, associated with amino acid metabolism and liver stress. Plasma from the H-MF cows contained higher β-hydroxybutyric acid, methionine sulfoxide, and phosphatidylcholine, supporting lipogenesis, whereas L-MF plasma showed increased 3-hydroxy-L-proline, indicating tissue catabolism. In milk, the L-MF cows had higher MA, while the H-MF cows exhibited elevated L-carnitine, linked to fatty acid β-oxidation. Metabolite trend analysis during rumen fluid–plasma–milk showed that 211 metabolites were classified into 8 profiles. Profile 1 had the largest number of metabolites whose levels were down-regulated from rumen to plasma and enriched in lipid metabolism. Profile 3 (mainly related to amino acid metabolism) and profile 4 (mainly related to energy metabolism) exhibited opposite trends from plasma to milk. In vitro, 200 μM of MA reduced the triglyceride content in BMECs and down-regulated lipogenic genes and their protein expression levels (fatty acid synthase, stearoyl-CoA desaturase and sterol regulatory element binding protein 1). These results highlight how rumen fluid, plasma, and milk metabolites collectively influence milk fat synthesis, with MA acting as a key regulator of lipid metabolism in mammary epithelial cells. Full article

The role of fatty acid transporter 4 (FATP4) in regulating lipid metabolism has been well studied. However, how it affects IMF deposition, especially in goats, remains poorly understood. Here, we cloned the whole coding sequence of the goat FATP4 gene and revealed its closest affinity to sheep by amino acid sequence blast analysis. In addition, we found that the FATP4 reached its highest expression level at day 6 of goat preadipocyte differentiation in vitro. Functionally, in cultured goat intramuscular preadipocytes, siRNA-induced FATP4 knockdown dramatically raised the mRNA expression of lipogenesis-related genes and encouraged lipid deposition. At the same time, FATP4 deficiency inhibited cell proliferation and significantly decreased apoptosis. Unexpectedly, although the overexpression of FATP4 promoted cell proliferation and suppressed apoptosis, it only slightly decreased cellular lipid deposition in goat intramuscular preadipocytes. For RNA-seq (performed on pooled cell samples with three technical replicates), a total of 467 differential genes (DEGs) were identified after silencing of FATP4 in goat preadipocytes, including 47 upregulated genes and 420 downregulated genes. These DEGs were mainly enriched in the signaling pathways of Focal adhesion, HIF-1, and PI3K-Akt by KEGG analysis. To validate these findings, knockdown of FATP4 increased the expression of phosphatidylinositol 3-kinase (PI3k) and vice versa. Convincingly, we rescued the phenotype observed in FATP4 knockout goat preadipocytes by blocking the PI3k-Akt signaling pathway with an AKT inhibitor (LY294002). In summary, in our in vitro model, FATP4 plays a crucial role in directing fatty acids toward cell proliferation (prioritized over cellular lipid deposition) via the PI3K-Akt signaling pathway in goat intramuscular preadipocytes. These findings provide preliminary mechanistic insights into the regulatory network of IMF formation at the cellular level, and offer theoretical clues for future research aimed at enhancing meat quality from the standpoint of IMF deposition. Full article

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disease worldwide with complex pathogenesis and no approved specific therapy. Siraitia grosvenorii is a widely used medicinal and edible herb, yet its efficacy and underlying mechanisms against MAFLD remain poorly defined. This study explored the protective effects and potential mechanisms of aqueous extract of Siraitia grosvenorii (AESG) on MAFLD. Based on ultra-high-performance liquid chromatography-linear trap quadrupole orbitrap mass spectrometry (UHPLC-LTQ-Orbitrap-MS) analysis, 38 components in AESG were tentatively assigned, with tetracyclic triterpene saponins being the most abundant. In high-fat diet (HFD)-induced MAFLD mice, AESG significantly attenuated body weight gain, reduced plasma total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) levels, and dramatically decreased hepatic triglyceride (TG) accumulation from 0.0141 mmol/g in the model group to 0.0063 mmol/g in the low-dose AESG group, corresponding to a reduction of 55.00%. AESG also alleviated plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and improved hepatocyte steatosis. Furthermore, AESG restored HFD-induced gut dysbiosis by enriching beneficial bacteria including Akkermansia and suppressing harmful bacteria such as Ruminococcus. In free fatty acids (FFA) stimulated HepG2 cells, AESG suppressed de novo lipogenesis via downregulating Fatty Acid Synthase (FASN), Acetyl-CoA Carboxylase (ACC) and Sterol Regulatory Element-Binding Protein 1c (SREBP1c), and enhanced antioxidant capacity via activating the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase 1 (HO-1)/Sirtuin 1 (SIRT1) pathway, thereby attenuating lipid accumulation and oxidative stress. In conclusion, AESG ameliorates MAFLD by inhibiting lipogenesis, improving oxidative stress, and regulating gut microbiota. These findings support Siraitia grosvenorii as a promising natural dietary intervention for MAFLD prevention and adjuvant therapy. Full article

Background/Objectives: Feeding with a ketogenic diet (KD), nutritionally devoid of carbohydrates, may be metabolically beneficial. The administration of a KD to mice after previous feeding with a high-fat, high-carbohydrate diet (HFD) induced weight loss, ketonemia, and glycemic normalization. Here, to compare organ-specific responses to KD, we analyzed lipogenic and gluconeogenic enzymes and genes in the liver and kidney of mice submitted to KD versus (i) HFD or (ii) a saccharose-enriched diet. Methods: Liver and kidney were from (i) mice fed a HFD followed by an 8-week switch to a chow diet (CD), KD continuation of HFD, and (ii) mice submitted to CD, KD, or a saccharose-enriched diet for 1 week. Protein expression levels were determined by Western blotting, and gene expression by qPCR. Hepatic lipid accumulation was visualized by red oil-O. Results: Switch to a KD led to a simultaneous decrease in lipogenic FASN (Fatty Acid Synthase), ACC (Acetyl-CoenzymeA Carboxylase), and its phosphorylated form (pACC-Ser79) in the liver and kidney. In parallel, we observed increased activating phosphorylation of AMPK, the kinase responsible for ACC phosphorylation. In the liver, but not in the kidney, the gluconeogenic rate-limiting enzyme G6Pase (Glucose 6-phosphatase) was repressed under a KD. The switch to a CD significantly reduced hepatic fat accumulation, while a switch to a KD did not allow a significant reversal of hepatic fat accumulation, suggesting resilience to hepatic fat loss under KD. Comparison of a KD versus saccharose-supplemented diet showed an opposite expression pattern of lipogenic enzymes. Conclusions: Administration of KD after previous HFD induced convergent repression of lipogenic enzymes in the liver and kidney, and specific repression of G6Pase in the liver, suggesting a role for kidney gluconeogenesis during KD. KD versus saccharose-supplemented diet had opposite effects on lipogenesis and glycemic control, but both induced loss of lean body mass. Full article

Microalgae and cyanobacteria are investigated for compounds that may relate to obesity and metabolic phenotypes, yet the evidence base remains scattered and inconsistently reported. We conducted a PRISMA-ScR scoping review of PubMed, Europe PMC, and OpenAlex and mapped eligible full-text studies to a controlled vocabulary covering intervention concepts, mechanistic pathway nodes, and obesity-related outcome domains. Of 2651 reports sought for full text, 936/2651 (35.3%) were not retrieved; therefore, evidence maps should be interpreted as conditioned on full-text accessibility. We included 836 studies and summarized study density (counts only) by population/model tier, mechanistic reporting depth, chemical class, and safety/toxin flags. The literature is concentrated in animal models (485 studies) and human studies (292), with fewer in vitro/ex vivo reports (59). Mechanistic reporting was often limited: 582 studies did not provide extractable mechanistic endpoints, whereas 254 reported biomarker or pathway “anchors”. Across intervention concepts, lipid/PUFA, carotenoids, phycobiliproteins, and polysaccharides were most common; within the anchored subset, inflammation (NF-κB), AMPK signaling, adipogenesis (PPARγ-related), and lipogenesis were the most frequently mapped nodes. Together, this evidence map clarifies where mechanistic anchoring and safety documentation are sparse and provides a clear starting point for downstream evaluation. Full article

Excessive lipid accumulation, a hallmark characteristic of high-fat diet (HFD)-induced obesity, has become a worldwide challenge, necessitating the exploration of secure and efficacious natural products for its intervention. In the present work, a polysaccharide (MCP) was extracted and purified from Mesembryanthemum crystallinum L., a novel halophyte, and its physicochemical properties, in vitro fermentation characteristics, lipid-lowering activity, and underlying mechanisms were systematically investigated. Physicochemical analysis revealed that MCP is an acidic polysaccharide, with galacturonic acid as the predominant monosaccharide component, broad molecular weight distribution, and a porous structural morphology. In vitro fermentation experiments demonstrated that MCP could be effectively utilized by human fecal microbiota, significantly promoting the yield of short-chain fatty acids (SCFAs), particularly butyrate at high concentrations, which outperformed inulin. 16S rDNA sequencing uncovered that MCP optimized microbiota composition by enriching SCFA-producing beneficial bacteria (Prevotella_9, Faecalibacterium) while suppressing opportunistic pathogens (Megamonas, Escherichia-Shigella). Metabolomic analysis of fermentation broth revealed that MCP significantly affected microbial glycerophospholipid metabolic pathways. Experiments in Caenorhabditis elegans (C. elegans) confirmed that MCP inhibited HFD-induced lipogenesis, which was linked to the regulation of the nhr-49/sbp-1-mediated lipogenesis pathway. For the first time, using an antibiotic-induced microbiota depletion model in C. elegans, the lipid-lowering effect of MCP was observed to disappear, suggesting a potential role of the gut microbiota in mediating this effect. This investigation establishes a scientific basis for MCP as a novel prebiotic or dietary supplement for managing obesity-related lipid accumulation. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming increasingly prevalent worldwide, particularly among individuals with obesity and type 2 diabetes (T2D). MASLD remains potentially reversible in the early phases but, without timely intervention, it can progress to metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis, which in turn may advance to cirrhosis and hepatocellular carcinoma over time. With no pharmacological treatments specifically indicated for MASLD, current therapeutic strategies include lifestyle modifications, including dietary modifications. Niacin and its molecular derivatives (collectively belonging to the vitamin B3 group) play a central role in metabolic processes, especially through their involvement in the biosynthesis of the oxidized form of nicotinamide adenine dinucleotide (NAD⁺). A growing body of preclinical evidence suggests that reduced NAD⁺ levels are a hallmark of MASLD, and that NAD⁺ precursors may help attenuate disease progression through multiple mechanisms, including sirtuin 1 (SIRT1)-mediated inhibition of hepatic lipogenesis. Although these findings from experimental models suggest a potential role for niacin and related molecular derivatives as a modulators of MASLD-related pathways, evidence from human studies remains limited and inconsistent. For instance, interventional studies evaluating niacin or molecular derivatives supplementation have reported variable findings, with several trials showing limited meaningful benefits on MASLD-related outcomes. Consequently, further well-designed, controlled trials are needed to clarify therapeutic efficacy, dose–response relationship, and the feasibility of integrating niacin derivatives into dietary or therapeutic strategies aimed at reducing liver fat and improving adverse metabolic outcomes. This review aims to (i) summarize mechanistic insights on the role of niacin as a source of NAD⁺ on experimental MASLD and (ii) critically evaluate the available human evidence on the effect of supplemental niacin and derivatives in the prevention of MASLD development and its progression to MASH and fibrosis. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide, arising from profound metabolic reprogramming and widespread epigenetic dysregulation. However, the role of epigenetic aberrations in modulating metabolic reprogramming and the interplay between cis-regulatory elements (CREs), such as promoters, enhancers and super-enhancers, and metabolic adaptation have not been systematically summarized. Therefore, this review aims to integrate current evidence to elucidate the mechanisms of how cis-regulatory elements (CREs) drive oncogenic and metabolic signals in HCC progression. For instance, enhancers and super-enhancers transcriptionally activate key metabolic genes involved in aerobic glycolysis (GLUT1, HK2, PKM2, LDHA), de novo lipogenesis (ACLY, FASN, ACC), glutaminolysis (SLC1A5, GLS), and nucleotide synthesis. Meanwhile, many metabolic intermediates, including acetyl-CoA, succinyl-CoA and lactate, act as cofactors or substrates for epigenetic modifiers, creating bidirectional feedback loops that reinforce CRE-driven malignant phenotypes. Therefore, aberrant CREs acts as “metabolic switches” that sense and respond to various metabolic conditions to sustain HCC growth. Consequently, targeted intervention against oncogenic CREs, such as super-enhancers or their co-activators, to disrupt CRE-mediated metabolic vulnerabilities, has emerged as a highly promising new paradigm for precision therapy in HCC. Full article

Obesity is characterized by abnormal adipose tissue expansion and energy metabolism imbalance. Browning of white adipose tissue (WAT), wherein white adipocytes acquire thermogenic properties similar to brown adipose tissue, represents a key mechanism for increasing energy expenditure. Although ginseng (Panax ginseng C.A. Meyer) is widely recognized as a health-promoting botanical, its role in WAT browning has not been fully elucidated. This review summarizes evidence that ginseng and its bioactive components regulate major thermogenic pathways, including β-adrenergic/cyclic adenosine monophosphate-protein kinase (cAMP-PKA) signaling, AMP-activated protein kinase (AMPK), and the peroxisome proliferator-activated receptor γ (PPARγ)/coactivator 1α (PGC-1α) axis, thereby upregulating key markers such as uncoupling protein 1 (UCP1), PR domain containing 16 (PRDM16) and type II iodothyronine deiodinase (DIO2). These effects promote mitochondrial function and fatty acid oxidation, reduce lipogenesis, alleviate inflammation, and improve insulin sensitivity, collectively fostering a microenvironment conducive to browning. Furthermore, fermentation has been found to enhance the bioactivity and thermogenic efficacy of ginseng. Recent evidence indicates that gut microbiota and their metabolites—such as short-chain fatty acids, unsaturated fatty acids, and bile acids—play a notable role in ginseng-induced thermogenesis via receptors including G-protein-coupled receptor 41/43 (GPR41/43), takeda G-protein-coupled receptor 5 (TGR5), and farnesoid X receptor (FXR). These multi-organ interaction networks involving the gut–fat, gut–liver, and gut–brain axes reflect the role of ginseng in integrating systemic metabolism. In summary, this review discusses the multi-level regulatory network through which ginseng promotes WAT browning, providing a mechanistic basis for its potential application in body weight and metabolic health management. Full article

Prostate cancer (PCa) progression is critically driven by androgen receptor (AR) signaling, which integrates hormonal cues with metabolic programs supporting tumor growth, survival, and therapy resistance. Emerging evidence suggests that intermittent fasting (IF) and related dietary interventions—such as time-restricted eating (TRE), alternate-day fasting (ADF), and fasting-mimicking diet (FMD)—modulate systemic metabolism, including reductions in insulin and insulin-like growth factor 1 (IGF-1), and induce intracellular nutrient stress that can influence AR activity, splice variant expression (e.g., AR-V7), and downstream metabolic pathways. This systematic literature review (Scopus, PubMed, Web of Science; publications up to December 2025; search terms: “prostate cancer,” “androgen receptor,” “AR splice variants,” “intermittent fasting,” “fasting mimicking diet”, “metabolism,” “therapy resistance”) summarizes preclinical and clinical studies addressing the impact of IF on AR signaling, lipogenesis, mitochondrial function, redox homeostasis, and therapy response. Preclinical studies indicate that IF can reduce AR expression, impair nuclear translocation, modulate AR splice variants such as AR-V7 via nutrient-sensitive splicing mechanisms, and enhance sensitivity to androgen deprivation therapy and AR-targeted agents. Mechanistically, IF-induced metabolic stress engages AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and sirtuin pathways, alters lipid and mitochondrial metabolism, and transiently increases reactive oxygen species (ROS), creating vulnerabilities in prostate tumor cells. Translational evidence suggests potential benefits of integrating IF with standard therapy, but effects may depend on fasting regimen, caloric intake, macronutrient composition, and patient metabolic context, including risk of lean mass loss. This review highlights the metabolic crosstalk between IF and AR signaling and emphasizes the need for future clinical studies incorporating biomarker-guided approaches and body composition monitoring to fully exploit this intersection for improved therapeutic outcomes in prostate cancer. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory subtype metabolic dysfunction-associated steatohepatitis (MASH) are now the most common types of chronic liver disease worldwide and major contributors to cirrhosis, hepatocellular carcinoma, and liver transplantation. The disease develops from systemic metabolic dysfunction, including obesity, insulin resistance, and dyslipidemia. These factors increase hepatic fatty acid influx and de novo lipogenesis, driving steatosis, inflammation, and progressive fibrosis. Lifestyle modification is the foundation of treatment. Even modest weight loss can improve steatosis and inflammatory activity, although long-term adherence is often limited. These challenges have accelerated interest in targeted pharmacologic therapy. Thyroid hormone receptor beta agonists such as resmetirom reduce hepatic fat, improve lipid parameters, and show histologic benefit. Peroxisome proliferator activated receptor (PPAR) agents have progressed from single isoform approaches to pan-PPAR activation. Lanifibranor has demonstrated dose-dependent improvements in steatosis, activity, and fibrosis and has achieved key regulatory endpoints. Additional metabolic therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), offer complementary benefits for weight, insulin sensitivity, and liver inflammation. These emerging options represent a promising shift toward disease modifying treatment for MASLD. Full article

The N88S mutation in human seipin causes a dominant motor neuron disease marked by ER stress and inclusion body formation, lipid imbalance, and oxidative damage. However, the metabolic mechanisms connecting these defects remain poorly understood. Previous proteomic profiling in our yeast model of N88S human seipinopathy revealed decreased protein levels of enzymes involved in the tricarboxylic acid cycle, fatty acid and carboxylic acid metabolism, and the glyoxylate cycle, suggesting impaired downstream utilization of peroxisome-derived acetyl-CoA. Guided by these findings, we investigated how peroxisomal function contributes to cellular dyshomeostasis. N88S seipin-expressing cells exhibited increased peroxisome abundance but defective routing of acetyl-CoA into mitochondrial and glyoxylate pathways, resulting in elevated reactive oxygen species (ROS), impaired glyoxylate cycle activation, and reduced metabolic adaptability to non-fermentable carbon sources. Loss of peroxisomes or forced cytosolic redirection of acetyl-CoA further exacerbated ER stress, ROS accumulation, lipid peroxidation, and the growth defect on N88S seipin-expressing cells, whereas inhibition of fatty acid synthesis mitigated oxidative damage. These findings demonstrate that N88S seipin triggers a futile cycle in which misrouted cytosolic acetyl-CoA drives lipogenesis, amplifying oxidative damage and ER stress. We conclude that defective peroxisome–mitochondria metabolic coupling and acetyl-CoA misrouting may represent central pathogenic mechanisms driving cellular dysfunction in N88S-linked seipinopathy. Full article

Primary liver cancer (PLC), commonly classified as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), is a highly aggressive malignancy with a dismal prognosis. Recent research has highlighted the crucial role of dysregulation of fatty acid metabolism in HCC progression and therapeutic resistance. Here, with a focus primarily on HCC, we review how alterations in the processes involving fatty acids dynamically contribute to the survival, proliferation, and development of the drug resistance of PLC cells. In particular, increased expression of fatty acid transporters, reprogramming of de novo lipogenesis, and altered fatty acid oxidation trigger the upregulation of oncogenic signaling pathways and adaptation to nutrient-deprived conditions inducing the rapid proliferation of PLC cells. Furthermore, fatty acid metabolism influences immune cell function and angiogenesis, thereby shaping the tumor microenvironment and promoting the progression of PLC. This review explores the complex relationship between fatty acid metabolism and the progression of PLC. It discusses future directions regarding the most promising druggable targets and their current status in clinical trials. Furthermore, it examines the advancement of innovative therapeutic strategies and highlights the significant challenges in targeting fatty acid metabolism. Finally, it discusses how precision therapies focused on fatty acid metabolism can be effectively integrated with current treatments. Full article

Terminalia bellirica extract (TBE) has long been utilized in Ayurvedic medicine across Indian and surrounding regions for diverse therapeutic applications. Despite its traditional prominence, systematic investigations addressing the anti-obesity efficacy and underlying mechanisms remain limited. In this study, we evaluated the anti-obesity potential of TBE using both 3T3-L1 adipocyte and high-fat diet (HFD)-induced mice model. In vitro studies using 3T3-L1 adipocytes demonstrated that TBE significantly inhibited lipid accumulation and downregulated key genes involved in adipogenesis and lipogenesis, while upregulating genes promoted lipolysis and energy metabolism. To validate these cellular effects in a physiological context, mice were randomly assigned to six groups: normal control (NC), HFD-induced obese (C), HFD with metformin (100 mg/kg b.w., PC), and HFD with TBE at 50, 100, and 200 mg/kg b.w. Consistent with the in vitro findings, TBE supplementation significantly reduced body weight gain, adipose tissue mass, and adipocyte size in HFD-induced obese mice. Taken together, these results indicate that TBE exerts anti-obesity effects through modulation of adipose tissue metabolic pathways, highlighting its therapeutic potential for obesity management. Full article