Search Results (602)

Perturbations in the tightly regulated processes of VLDL biosynthesis and secretion can directly impact both liver and cardiovascular health. Patients with metabolic disorders have an increased risk of developing hepatic steatosis, which can lead to cirrhosis. These associated metabolic risks underscore the importance of discerning the role of different cellular proteins involved in VLDL biogenesis, transport, and secretion. Small VCP-Interacting Protein (SVIP) has been identified as a component of VLDL transport vesicles and VLDL secretion. This study evaluates the cellular effects stemming from the CRISPR-Cas9-mediated depletion of SVIP in rat hepatocytes. The SVIP-knockout (KO) cells display an increased VLDL retention with elevated intracellular levels of ApoB100 and neutral lipid staining. RNA sequencing studies reveal an impaired PPARα and Nrf2 signaling in the SVIP KO cells, implying a state of metabolic reprograming, with a shift from fatty acid uptake, synthesis, and oxidation to cells favoring the activation of glucose by impaired glycogen storage and increased glucose release. Additionally, SVIP KO cells exhibit a transcriptional profile indicative of acute phase response (APR) in hepatocytes. Many inflammatory markers and genes associated with APR are upregulated in the SVIP KO hepatocytes. In accordance with an APR-like response, the cells also demonstrate an increase in mRNA expression of genes associated with protein synthesis. Together, our data demonstrate that SVIP is critical in maintaining hepatic lipid homeostasis and metabolic balance by regulating key pathways such as PPARα, Nrf2, and APR. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a prevalent, multisystem disease affecting approximately 30% of adults worldwide. Obesity, along with dyslipidemia, type 2 diabetes mellitus, and hypertension, are closely intertwined with MASLD. In people with obesity, MASLD prevalence is estimated to be about 75%. Despite various approaches to MASLD treatment, dietary changes remain the most accessible and safe interventions in MASLD, especially in obese and overweight patients. Whey proteins are rich in bioactive compounds, essential amino acids with antioxidant properties, offering potential benefits for MASLD prevention and management. This state-of-the-art review summarizes whey protein impacts on a spectrum of MASLD-related manifestations, such as obesity, impaired glucose and lipid metabolism, hypertension, liver injury, oxidative stress, and inflammation. The results obtained in clinical environments, with a focus on meta-analysis, propose whey protein supplementation as a promising strategy aimed at managing multifaced MASLD disorders. Well-designed cohort studies are needed for validation of the efficacy and long-term safety of whey proteins in MASLD patients. Full article

Insulin resistance is a fundamental pathophysiological mechanism contributing to the development of type 2 diabetes and metabolic syndrome. Recently, attention has focused on mitochondria’s role in glucose and lipid metabolism. Mitochondrial dysfunction is strongly associated with impaired energy metabolism and elevated oxidative stress. We investigated the mitochondrial DNA (mtDNA) copy number in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in insulin-sensitive (IS) and insulin-resistant (IR) individuals. Twenty-seven paired adipose tissue biopsies were obtained during elective abdominal surgery. DNA and RNA were extracted, and mtDNA copy number was quantified using Real-Time PCR. We found that mtDNA content in VAT was approximately two-fold lower than in SAT. Furthermore, in IR individuals, mtDNA copy number was significantly reduced in both SAT and VAT compared to IS subjects. A strong positive correlation was observed between mtDNA content in VAT and body mass index (BMI), and a negative correlation was found with the QUICKI index. Additionally, mtDNA copy number in VAT positively correlated with the expression of several genes involved in insulin signalling, lipid metabolism, and other metabolic pathways. These findings underscore the central role of mitochondrial function in VAT in the context of metabolic disorders and suggest that targeting mitochondrial regulation in this tissue may represent a promising therapeutic approach. Full article

Familial dysbetalipoproteinemia (FD) is a prevalent and highly atherogenic hyperlipoproteinemia associated with the ε2/ε2 APOE genotype or rare APOE variants. The contributions of additional genetic and clinical factors to the FD phenotype remain unclear. We investigated these factors in both autosomal recessive and autosomal dominant forms of FD. Targeted (n = 4666) and exome (n = 194) sequencing were used to identify the ε2/ε2 APOE genotype or rare FD-causative APOE variants. Twenty-four lipid-related genes and forty variants included in a polygenic risk score for hypertriglyceridemia (HTG) were analyzed. FD was defined by the presence of FD variants and triglycerides (TG) ≥ 1.5 mmol/L (main study group). The comparison group consisted of patients with FD variants but TG < 1.5 mmol/L. Univariable and multivariable regression analyses were performed. A total of 71 unrelated subjects were identified (45.1% male, median age 50 years). FD was diagnosed in 52 patients, while 19 had FD variants only. Age (p = 0.019), elevated polygenic risk for HTG (p = 0.001), and the presence of metabolic syndrome components (p = 0.014) were independently associated with the FD phenotype. TG levels were significantly associated with polygenic burden (0.05 mmol/L per percentile), the presence of additional rare lipid-related variants (7.0 mmol/L), and glucose metabolism disorders (3.62 mmol/L), together explaining 30% of TG variance in cross-validated model. These results highlight the interplay of genetic and metabolic factors in FD development and support the integration of HTG genetic risk scores and metabolic control into personalized FD management. Full article

β-hydroxybutyrate (BHB) is the most abundant ketone body produced during ketosis, a process initiated by glucose depletion and the β-oxidation of fatty acids in hepatocytes. Traditionally recognized as an alternative energy substrate during fasting, caloric restriction, and starvation, BHB has gained attention for its diverse signaling roles in various physiological processes. This review explores the emerging therapeutic potential of BHB in the context of sarcopenia, metabolic disorders, and neurodegenerative diseases. BHB influences gene expression, lipid metabolism, and inflammation through its inhibition of Class I Histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs), specifically HCAR2 and FFAR3. These actions lead to enhanced mitochondrial function, reduced oxidative stress, and regulation of inflammatory pathways, with implication for muscle maintenance, neuroprotection, and metabolic regulation. Moreover, BHB’s ability to modulate adipose tissue lipolysis and immune responses highlight its broader potential in managing chronic metabolic conditions and aging. While these findings show BHB as a promising therapeutic agent, further research is required to determine optimal dosing strategies, long-term effects, and its translational potential in clinical settings. Understanding BHB’s mechanisms will facilitate its development as a novel therapeutic strategy for multiple organ systems affected by aging and disease. Full article

Chronic high-fat diet (HFD) feeding in male rats causes significant metabolic as well as inflammatory disturbances, including obesity, insulin resistance, dyslipidemia, liver and kidney dysfunction, oxidative stress, and hypothalamic dysregulation. This study assessed the therapeutic effects of chlorogenic acid (CGA), a natural polyphenol, administered at 10 mg and 100 mg/kg/day for the last 4 weeks of a 12-week HFD protocol. Both CGA doses reduced body weight gain, abdominal circumference, and visceral fat accumulation, with the higher dose showing greater efficacy. CGA improved metabolic parameters by lowering fasting glucose and insulin and enhancing lipid profiles. CGA suppressed orexigenic genes (Agrp, NPY) and upregulated anorexigenic genes (POMC, CARTPT), suggesting appetite regulation in the hypothalamus. In abdominal white adipose tissue (WAT), CGA boosted antioxidant defenses (SOD, CAT, GPx, HO-1), reduced lipid peroxidation (MDA), and suppressed pro-inflammatory cytokines including TNF-α, IFN-γ, and IL-1β, while increasing the anti-inflammatory cytokine IL-10. CGA modulated inflammatory signaling via upregulation of miR-146a and inhibition of IRAK1, TRAF6, and NF-κB. It also reduced apoptosis by downregulating p53, Bax, and Caspase-3, and restoring Bcl-2. These findings demonstrate that short-term CGA administration effectively reverses multiple HFD-induced impairments, highlighting its potential as an effective therapeutic for obesity-related metabolic disorders. Full article

Prosaposin (PSAP), a multifunctional protein, plays a central role in various biological processes and diseases. It is the precursor of lysosomal activating protein, which is important for lipid metabolism and glucose metabolism. PSAP is implicated in cell signaling, neuroprotection, immunomodulation, and tumorigenesis. In neurological disorders, PSAP acts as a neurotrophic factor influencing nerve cell survival and synapse growth, and its dysfunction is associated with a variety of diseases. It modulates immune responses and macrophage functions, affecting inflammation and immune cell activities. The role of PSAP in cancers is complex, because it promotes or inhibits tumor growth depending on the context and it serves as a potential biomarker for various malignancies. This review examines current research on the functional and pathological roles of PSAP, emphasizing the importance of PSAP in Gaucher disease, neurodegenerative diseases, cardiovascular diseases, and cancer. In order to develop targeted therapies for various diseases, it is essential to understand the mechanisms of action of PSAP in different biological processes. Full article

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition worldwide and represents a major global health challenge. Pharmacological and pharmacodynamic results indicate that aspirin eugenol ester (AEE) performs various pharmacological activities. However, it is unclear whether AEE can ameliorate the NAFLD. This study investigated the ameliorative effects of AEE on glucose and lipid metabolism disorders by in vitro and in vivo experiments. In the cellular model, TC increased to 0.104 μmol/mg and TG increased to 0.152 μmol/mg in the model group, while TC decreased to 0.043 μmol/mg and TG decreased to 0.058 μmol/mg in the AEE group. In the model group, the area occupied by lipid droplets within the visual field was significantly elevated to 17.338%. However, the administration of AEE resulted in a substantial reduction in this area to 10.064%. AEE significantly reduced the lipid droplet area and TC and TG levels (p < 0.05), increased bile acids in the cells and in the medium supernatant (p < 0.05), and significantly up-regulated the expression of LRH-1, PPARα, CYP7A1, and BSEP mRNA levels (p < 0.05) compared to the model group. In the animal model, different doses of AEE administration significantly down-regulated the levels of TC, TG, LDL, GSP, and FBG (p < 0.05) compared to the high-fat-diet (HFD) group, and 216 mg/kg of AEE significantly improved hepatocellular steatosis, attenuated liver injury, and reduced the area of glycogen staining (p < 0.05). In the HFD group, the glycogen area within the visual field exhibited a significant increase to 18.250%. However, the administration of AEE resulted in a notable reduction in the glycogen area to 13.314%. Liver and serum metabolomics results show that AEE can reverse the metabolite changes caused by a HFD. The major metabolites were involved in seven pathways, including riboflavin metabolism, glycerophospholipid metabolism, tryptophan metabolism, primary bile acid biosynthesis, biosynthesis of unsaturated fatty acids, nicotinate and nicotinamide metabolism, and tryptophan metabolism. In conclusion, AEE had a positive regulatory effect on NAFLD. Full article

Background/Objectives: Depression is frequently comorbid with obesity. We previously showed that astrocyte-mediated hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behaviors in obese murine models. However, it remains unclear if the metabolic disorder-induced depressive phenotypes and astrocytic maladaptation in the ventral hippocampus (vHPC) could be reversed following the amelioration of key metabolic impairments such as insulin resistance and dyslipidemia. Method: Male mice were fed a high-fat diet (HFD) for 12 weeks, followed by either continued HFD feeding (HFD/HFD group) or a switch to a standard diet for 4 weeks (HFD/SD group). Results: Results showed that HFD/HFD mice displayed not only glucose/lipid metabolic dysfunction, but also depression-like behaviors. In contrast, HFD/SD mice showed improvements in metabolic disorders and depressive phenotypes. Mechanistically, dietary fat reduction restored astrocyte morphology and glutamate transporter expression (GLT-1, GLAST) in the vHPC and suppressed neuroinflammatory signaling, as evidenced by reduced levels of phospho-IKK, TNF-α, IL-1β, and IL-6 in the vHPC. Conclusions: These findings suggest that dietary fat reduction reverses obesity-induced depressive phenotypes, astrocytic deficits, at least in part via suppression of neuroinflammation through the NF-κB signaling pathway. Full article

Insulin, traditionally recognized for its pivotal role in glycemic regulation, exerts extensive effects beyond glucose homeostasis, influencing multiple physiological systems. This narrative review explores the multifaceted actions of insulin, emphasizing its impact on skeletal muscle remodeling, protein and lipid metabolism, growth, reproductive health, and the central nervous system. Methods: An in-depth review of articles with evidence-based research discussing insulin actions beyond glycemic control was conducted in this review paper. Results: Insulin directly influences lipid and protein metabolism as well as growth hormone levels. This hormone provides a protective effect on the skeletal and central nervous systems, helping to maintain homeostasis and potentially reducing the risk of certain disorders such as Alzheimer’s disease. The significance of insulin balance in the reproductive system is also crucial, with recent research indicating that insulin plays a role in worsening symptoms and complications associated with polycystic ovary syndrome. This review underscores the importance of maintaining proper insulin levels to lower the risk of insulin resistance. Ongoing research aims to deepen our understanding of insulin’s functions, which are essential for preventing specific diseases and developing new treatment strategies. Conclusions: Insulin’s action extends far beyond glucose metabolism, affecting many systems and preventing pathological changes in some. Full article

The progression of type 2 diabetes mellitus (T2DM) is shaped by a multifaceted interplay among genetic, behavioral, and environmental factors, alongside gut dysbiosis. Cinnamon, being abundant in polyphenols and flavonoids, shows significant antioxidant effects. Studies have substantiated that cinnamon contributes to the management of glucose and lipid metabolism. However, the anti-diabetic efficacy of cinnamon is not completely understood. The objective of this research was to clarify the anti-diabetic mechanism associated with cinnamon extract through a combination of chemical profiling, network pharmacology, and in vivo investigations. The results indicated that 32 chemical ingredients, including quercetin, were identified through UPLC-Q-TOF-MS. Network pharmacology revealed that 471 targets related to 14 compounds were screened. The analysis of GO enrichment revealed that the primary pathways were notably enhanced in the metabolism of insulin and glucose. In vivo analyses showed that cinnamon could effectively alleviate hyperglycemia, insulin resistance, and lipid metabolism abnormalities via increased relative abundance of Akkermansia and Ligilactobacillus at the genus level and a decreased Firmicutes/Bacteroidetes ratio at the phylum level. Moreover, cinnamon reduced the serum levels of lipopolysaccharide (LPS) and proinflammatory cytokines (IL-6 and TNF-α) and significantly increased the colon Zonula occludens-1 (ZO-1) and occludin protein levels. It was also observed that cinnamon improved the fecal SCFA levels (acetic, propionic, butyric, valeric and caproic acid), while also modifying the bile acid (BA) profile and increasing the conjugated-to-unconjugated BA ratio. The Western blotting analysis further demonstrated that cinnamon activated intestinal FXR/FGF15 and hepatic PI3K/AKT signaling pathways. In summary, the finding confirmed that cinnamon ameliorated glucose and lipid metabolism disorders by safeguarding the intestinal barrier and modulating the gut microbiota and metabolites, thereby activating intestinal FXR/FGF15 and hepatic PI3K/AKT signaling pathways. Full article

Berberine, a bioactive isoquinoline alkaloid derived from medicinal plants such as Berberis and Coptis species, shows significant promise for managing obesity and associated metabolic disorders. This review synthesizes evidence on its modulation of AMP-activated protein kinase (AMPK) signaling, gut microbiota composition, lipid metabolism, and adipokine networks, elucidating how these actions converge to suppress adipogenesis and improve insulin sensitivity. Metabolomic profiling reveals critical shifts in bile acid metabolism, short-chain fatty acid production, and mitochondrial function. Recent studies also highlight berberine’s anti-inflammatory effects and regulatory influence on glucose homeostasis. Despite its promise, challenges in oral bioavailability and drug interactions necessitate the development of advanced delivery strategies. We further discuss nanoformulations and multi-omics approaches, which integrate data from genomics, transcriptomics, proteomics, and metabolomics, provide new insights into berberine’s mechanisms, and may guide personalized therapeutic applications. While promising, further studies are needed to validate these findings in humans and translate them into effective clinical strategies. Full article

Background/Objectives: Long non-coding RNAs (lncRNAs) play significant roles in tissue development and disease progression and have emerged as crucial regulators of gene expression. The hepatocyte nuclear factor alpha antisense RNA 1 (HNF1A-AS1) lncRNA is a particularly intriguing regulatory molecule in liver biology that is involved in the regulation of cytochrome P450 enzymes via epigenetic mechanisms. Despite the growing recognition of lncRNAs in liver disease, the comprehensive role of HNF1A-AS1 in liver function remains unclear. This study aimed to investigate the roles of the mouse homolog of the human HNF1A-AS1 lncRNA HNF1A opposite strand 1 (Hnf1aos1) in liver function, gene expression, and cellular processes using a mouse model to identify potential therapeutic targets for liver disorders. Methods: The knockdown of Hnf1aos1 was performed in in vitro mouse liver cell lines using siRNA and in vivo livers of AAV-shRNA complexes. Changes in the global expression landscapes of mRNA and proteins were revealed using RNA-seq and proteomics, respectively. Changes in the selected genes were further validated via real-time quantitative polymerase chain reaction (RT-qPCR). Phenotypic changes were assessed via histological and absorbance-based assays. Results: After the knockdown of Hnf1aos1, RNA-seq and proteomics analysis revealed the differential gene expression of the mRNAs and proteins involved in the processes of molecular transport, liver regeneration, and immune signaling pathways. The downregulation of ABCA1 and SREBF1 indicates their role in cholesterol transport and fatty acid and triglyceride synthesis. Additionally, significant reductions in hepatic triglyceride levels were observed in the Hnf1aos1-knockdown group, underscoring the impact on lipid regulation. Notably, the knockdown of Hnf1aos1 also led to an almost complete depletion of CYP7A1, the rate-limiting enzyme in bile acid synthesis, highlighting its role in cholesterol homeostasis and hepatotoxicity. Histological assessments confirmed these molecular findings, with increased hepatic inflammation, hepatocyte swelling, and disrupted liver architecture observed in the Hnf1aos1-knockdown mice. Conclusions: This study illustrated that Hnf1aos1 is a critical regulator of liver health, influencing both lipid metabolism and immune pathways. It maintains hepatic lipid homeostasis, modulates lipid-induced inflammatory responses, and contributes to viral immunity, indirectly affecting glucose and lipid metabolic balance. Full article

Metabolic dysregulation involving glucose and lipids is closely associated with chronic diseases such as type 2 diabetes mellitus. Emerging evidence highlights the regulatory role of bile acid (BA)–gut microbiota interactions in these metabolic disorders. The gut microbiota orchestrates the biotransformation of primary BAs into bioactive secondary BAs, which function as endocrine signaling molecules by activating the nuclear farnesoid X receptor (FXR) and G protein-coupled membrane receptor (TGR5), forming a communication network essential for metabolic homeostasis. BAs also reciprocally modulate gut microbiota composition. This BA–gut microbiota co-metabolism has emerged as a promising therapeutic target for lipid metabolism disorders. This comprehensive review examines the bidirectional interplay between gut microbiota and BA metabolism, focusing on microbial transformation of BAs, host–microbial co-regulatory pathways and mechanisms of BA metabolism, and the therapeutic implications of modulating the gut microbiota–BA axis in addressing glucose and lipid metabolism disorders. The synthesis of current evidence aims to elucidate the intricate crosstalk between microbial ecology and host metabolism mediated by BA signaling pathways, thereby exploring novel therapeutic intervention strategies. Full article

In women, gonadal hormones play a crucial regulatory role in body fat distribution and glucose–lipidic homeostasis, which are closely associated with the hepatic steatogenesis and intrahepatic inflammatory pathways. Accumulating evidence supports the idea that hepatic health is closely linked to endocrine ovarian function through hormonal, metabolic, and immunological communications, collectively known as the “ovary–liver axis”. This review presents the molecular mechanisms involved in sex hormone synthesis, metabolism, and signaling pathways along the ovary–liver axis, focusing on dysregulated mechanisms that may contribute to common disorders and, specifically to hepatic derangements in the context of altered ovarian function. Additionally, we analyzed epidemiological evidence supporting the ovary–liver axis, specifically examining meta-analytic studies exploring the connection between polycystic ovary syndrome and metabolic dysfunction-associated steatotic liver disease (MASLD). We also discuss studies linking hypogonadism with liver health, with a specific focus on Turner syndrome and MASLD. Furthermore, we explore the impact of menopause on liver health. Our integrated molecular and epidemiological approach identifies important clinical and public health implications, aiming to uncover potentially innovative interventions and effective strategies for managing disease progression. However, unexplored areas within the ovary–liver axis highlight the need for further research on causal pathways. Full article