Search Results (233)

Heat-inactivated probiotics, also known as postbiotics, have emerged as an alternative to live probiotics, and have been shown to be good therapeutic tools for the management and treatment of metabolic dysfunctions such as obesity and type 2 diabetes (T2D). The present study aimed to assess the anti-obesogenic and anti-diabetic properties of heat-inactivated Pediococcus acidilactici pA1c^® (pA1c^®HI) in mice fed a high-fat diet (HFD). The animals were given an HFD or HFD enriched with either the probiotic alive pA1c^® or the postbiotic pA1c^®HI. Body weight (BW), serum biochemical markers, gene expression, and histological changes were determined following 15 weeks of supplementation. The postbiotic pA1c^®HI exerted a similar effect on glucose metabolism to that exerted by pA1c^® supplementation. Nevertheless, we observed that pA1c^®HI supplementation maintained BW, attenuated adipogenesis, and protected the mice from liver damage more efficiently than pA1c^®. Similarly, in adipose tissue, pA1c^®HI significantly downregulated markers of de novo lipogenesis (DNL) and fat storage. The observed results show that pA1c^®HI administration was even more effective in mitigating the HFD’s detrimental effects than pA1c^® supplementation, and therefore, the viability of this Pediococcus acidilactici CECT 9879 strain is not required for preserving its beneficial properties in the context of obesity and T2D. Full article

Acetate is naturally produced in the rumen through feed degradation and fermentation. It serves as a primary energy source for ruminants and as a key substrate for de novo fatty acid synthesis in the mammary gland. The interaction of exogenous acetate with different animal and dietary factors is an area of growing interest, as it may have significant implications for milk fat synthesis. This study aimed to assess the effect of two diet fermentability levels on the short-term response of lactation to acetate supplementation in dairy cows. Eight ruminally cannulated multiparous European Holstein cows were randomly assigned to treatments in a crossover design that tested the effect of diet fermentability, acetate supply, and their interaction. Using corn silage as the only forage source and a constant forage-to-concentrate ratio, high-fermentability (HF) and low-fermentability (LF) diets were formulated. Acetate supply was investigated by infusing ruminally 10 moles of sodium acetate/d (ACE) or an equimolar infusion of control (CON). Therefore, the treatments were as follows: LF + CON; LF + ACE; HF + CON; and HF + ACE. No interactions between acetate and diet fermentability were found on performance variables. Acetate infusion decreased dry matter intake (DMI), milk yield, and milk protein yield and content but did not affect milk fat yield; however, it increased milk fat concentration, and this response tended to be more pronounced in the HF diet. Acetate infusions increased plasma β-hydroxybutyrate in the HF diet, but not in the LF diet, and increased plasma non-esterified fatty acid, which was likely a lipolysis response to reduced DMI and decreased energy balance. This study demonstrates that acetate availability can be a constraint on mammary lipogenesis, even with adequate dietary fiber. Full article

Non-alcoholic fatty liver disease (NAFLD) is characterized by an accumulation of fat in hepatocytes, and it may progress, under additional triggering factors, to non-alcoholic steatohepatitis (NASH). Effective strategies to counteract this progression are essential, especially considering that at the moment, there is a lack of approved pharmacological therapies. Our previous study showed that the daily consumption of Navelina oranges significantly reduced hepatic steatosis in patients with Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Starting with our previous study, here, we have investigated the molecular targets through which Hesperidin (HE), a citrus flavanone, is able to prevent the progression of NAFLD to NASH using an in vitro model. In Hepa-RG cells exposed to NAFLD Promoting Agents, HE reduced lipid droplet accumulation (~35%) and suppressed de novo lipogenesis, with decreased expression of FASN (0.62 ± 0.06 vs. 0.39 ± 0.03 at 100 µg/mL) and SCD1 (0.05 ± 0.001 vs. 0.03 ± 0.004 at 50 µg/mL). HE also enhanced fatty acid oxidation by increasing SIRT1 (0.73 ± 0.16 vs. 2.36 ± 0.10 at 50 µg/mL) and PGC1α (0.71 ± 0.03 vs. 0.89 ± 0.003 at 50 µg/mL). In LX-2 cells, HE downregulated COL1A1 (1.48 ± 0.10 vs. 0.90 ± 0.11 at 100 µg/mL) and α-SMA (1.21 ± 0.16 vs. 0.76 ± 0.07 at 75 µg/mL) and upregulated MMP3 (0.64 ± 0.05 vs. 0.98 ± 0.07) and MMP9 (0.99 ± 0.005 vs. 2.61 ± 0.16 at 100 µg/mL). In conclusion, HE may offer a promising approach for NAFLD/NASH prevention and treatment, demonstrating in vitro its potential to reduce hepatic steatosis and fibrosis. Full article

Background/Objectives: Hepatic steatosis, characterized by abnormal fat accumulation in the liver, is a major health concern with limited effective treatments. Goat milk whey proteins have demonstrated various therapeutic benefits. This study aimed to evaluate the hepatoprotective effects of goat whey protein hydrolysate (GWPH) on high-fructose corn syrup (HFCS)-induced hepatic steatosis in a murine model. Methods: The GWPH was prepared through enzymatic hydrolysis using Alcalase^® and divided into fractions: GWPH03 (<3 kDa), GWPH0310 (3–10 kDa), GWPH1030 (10–30 kDa), and GWPH30 (>30 kDa). These fractions were administered to respective GWPH treatment groups at 200 mg/kg b.w/day via intragastric gavage for 8 weeks, with HFCS provided to all groups except the Naïve group. After dietary intervention, an oral glucose tolerance test (OGTT) was performed, and the mice were then sacrificed for further analysis. Results: Our results demonstrate that GWPH mitigates HFCS-induced hepatic steatosis, reduces body weight gain, improves glucose homeostasis, alleviates liver injury, and regulates hepatic lipid metabolism. Notably, GWPH treatment significantly suppressed hepatic fatty acid synthase (FASN) expressions, indicating reduced de novo lipogenesis (DNL). Molecular docking of the identified peptides from GWPH—particularly PFNVYNVV, which showed strong binding affinity for KHK—suggests that it has potential as a competitive inhibitor of fructose metabolism. Conclusions: Collectively, our findings suggest that GWPH and its derived peptides could be promising candidates for managing hepatic steatosis and related metabolic abnormalities. Full article

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), previously referred to as Non-Alcoholic Fatty Liver Disease (NAFLD), is a prevalent chronic liver condition strongly linked to Type 2 Diabetes Mellitus (T2DM) and obesity. Globally, MASLD is the most common cause of chronic liver disease. The bidirectional relationship between MASLD and T2DM underscores the pivotal role of insulin resistance in disease progression, which contributes to hepatic steatosis, oxidative stress, and inflammation, forming a vicious cycle. MASLD is also associated with heightened risks of cardiovascular and chronic kidney diseases, necessitating comprehensive treatment approaches. While lifestyle interventions and weight loss remain the cornerstone of management, their sustainability is challenging. This review highlights the evolving pharmacological landscape targeting MASLD and its advanced form, Metabolic Dysfunction-Associated Steatohepatitis (MASH). Currently, Resmetirom is the only FDA-approved drug for MASH. Current and investigational therapies, including insulin-sensitizing agents like peroxisome proliferator-activated receptor (PPAR) agonists, glucose-lowering drugs such as sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), drugs that target intermediary metabolism such as Vitamin E, de novo lipogenesis inhibitors, and emerging agents targeting the gut-liver axis and oxidative stress, are explored. These therapies demonstrate promising effects on hepatic steatosis, inflammation, and fibrosis, providing new avenues to address the multifaceted pathophysiology of MASLD. Full article

In hepatology, there is growing interest in identifying the mechanisms and risk factors underlying liver diseases with increasing incidence, with particular focus on metabolic dysfunction-associated steatotic liver disease (MASLD) and its complications. Simple sugars have been recognized as key contributors to liver injury and disease progression, not only in the context of MASLD but also beyond. As a result, numerous studies have aimed to elucidate their role in liver pathophysiology. Specifically, simple sugars have been associated with pivotal mechanisms involved in the onset of liver diseases, including inflammation, de novo lipogenesis, oxidative stress, insulin resistance, and dysbiosis with increased intestinal permeability. These mechanisms collectively contribute to a significant association between simple sugar intake and liver diseases of varying stages and severity. The scientific evidence available to date has not only clarified potential pathogenic mechanisms and clinical correlations but also led to the identification of potential therapeutic targets, encompassing both lifestyle interventions and molecular approaches. This review aims to provide a comprehensive analysis of the associations between simple sugar intake, liver injury, and liver diseases. To this end, we conducted an extensive review of the literature, selecting the most relevant and up-to-date studies on the topic. Full article

The effects of low-fat dairy products on insulin resistance (IR), hepatic steatosis, and gut microbiota composition in high-fat diet (HFD)-fed obese mice were examined. C57BL/6 male mice (n = 16/group) were fed a high-fat diet (HFD, 45% fat) or HFD supplemented with either fat-free milk (MILK), fat-free yogurt (YOG), or reduced-fat (19% milk fat) cheddar cheese (CHE) at 10% of the total energy intake for 8 weeks. Body weight, fat mass, liver lipids, and metabolic enzymes were evaluated. Compared with HFD, MILK reduced homeostatic assessment of insulin resistance along with increased hepatic insulin signaling and decreased hepatic gluconeogenic enzymes. YOG and MILK decreased hepatic triacylglycerol content and lipid droplet size, while CHE had no effect. In the liver, MILK and YOG downregulated de novo lipogenesis enzymes. In MILK, fat oxidation capacity was elevated. Compared with HFD, liver lipidomic analysis in MILK and YOG revealed unique profiles of decreased proinflammatory lipid species, including ceramides. Dairy feeding elicited an increase in beneficial bacteria, such as Streptococcus in YOG and Anaero-tignum in MILK, as shown by 16S rRNA sequencing of gut microbiota. In conclusion, the ability of milk and yogurt to reduce hepatic steatosis in HFD mice may be explained, at least in part, by the regulation of the gut microbiome and liver lipidome. Full article

Biochemical alterations linked to metabolic syndrome (MetS), type 2 diabetes (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD) may be brought on by the Western diet. Based on research conducted over the past decade, fructose is one of the main culprits. Over 80% of ingested fructose is metabolized by the liver at first pass, where it stimulates de novo lipogenesis (DNL) to drive hepatic triglyceride (TG) synthesis, which contributes to MASLD, hepatic insulin resistance (IR), and dyslipidemia. Fructose reduction produces quick and significant amelioration in these metabolic disturbances. We hereby propose potential overarching processes that can link these pathways to signaling disruption by the critical metabolic sensor AMP-activated protein kinase (AMPK). We proffer that when large amounts of fructose and glucose enter the liver, triose fluxes may be sufficient to produce transient increases in methylglyoxal (MG), allowing steady-state concentrations between its production and catabolism by glyoxalases to be high enough to modify AMPK-sensitive functional amino acid residues. These reactions would transiently interfere with AMPK activation by both AMP and aldolase. Such a sequence of events would boost the well-documented lipogenic impact of fructose. Given that MG adducts are irreversible, modified AMPK molecules would be less effective in metabolite sensing until they were replaced by synthesis. If proven, this mechanism provides another avenue of possibilities to tackle the problem of fructose in our diet. We additionally discuss potential multimodal treatments and future research avenues for this apparent hepatic AMPK malfunction. Full article

The liver’s crucial role in methylglyoxal (MG) metabolism is frequently overlooked in the literature. We present a perspective that enhances the current understanding of the role of methylglyoxal (MG) and the glyoxalase cycle in the pathogenesis of insulin resistance and obesity, ultimately leading to type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). Fructose may be a significant substrate contributing, particularly in contemporary times, to the flux of trioses in the liver, accounting for a substantial portion of MG production. The steady-state concentration of MG—and the subsequent modification of proteins—would then be determined by the flux of trioses, their utilization in lipogenesis, and their decomposition into MG, which is further converted into D-lactate by glyoxalase enzymes GLO1 and GLO2. Consequently, enhancing the activity and/or expression of GLO1 could potentially mitigate the adverse effects of fructose in the liver. Additional research and validation are required to confirm these biological pathways. These arguments are in favor of further research into safe and efficient ways to activate the glyoxalase pathway to lessen the negative effects of fructose metabolism that lead to insulin resistance (IR) and its related repercussions. Full article

Background/Objectives: Disrupted glucose uptake, oxidative stress, and increased de novo lipogenesis are some of the key features of metabolic dysfunction-associated fatty liver disease (MASLD). The modulation of these pathogenic mechanisms using extracts from natural and sustainable sources is a promising strategy to mitigate disease progression. This study aimed to evaluate the effects of Prunus domestica L. subsp. syriaca extract on these processes, taking advantage of a cell-based model of steatotic hepatocytes (HepG2-OA) that recapitulates some key pathophysiological features of MASLD. Methods: The HepG2-OA cell model was generated by treating cells for 7 days with 100 μM oleic acid (OA). The effect of different concentrations (0.01, 0.1, 0.5, and 1 mg/mL) of P. domestica extract was assessed through MTT assay (cell viability), flow cytometry (glucose uptake and reactive oxygen species, ROS, production), spectrophotometry (lipid accumulation), and qRT-PCR (expression of selected genes). Results: P. domestica extract exhibited no cytotoxicity at any tested concentration after 24 and 48 h in the HepG2-OA cells. The extract increased glucose uptake in a dose-dependent fashion after both 6 and 24 h. Additionally, the extract reduced lipid accumulation and downregulated the expression of key lipogenic genes (DGAT1 and FASN). Furthermore, in the HepG2-OA cells, P. domestica extract reduced ROS production and downregulated the expression of oxidative stress-related genes (SOD and CAT). Conclusions: P. domestica extract positively modulated some key molecular mechanisms associated with glucose metabolism, lipogenesis, and oxidative stress, supporting its potential as a nutraceutical candidate for MASLD management. Full article

Endometrial cancer (EC) is a complex gynecologic malignancy that requires a deeper understanding of its molecular basis to improve therapeutic strategies. In this study, we investigated the role of fatty acid (FA) reprogramming in the progression of EC. We analyzed FA profiles to identify the stage-specific changes and gene expression profiles of key enzymes involved in FA synthesis, desaturation, elongation, transport, and oxidation at different stages of EC. Our results show that EC tissues have lower levels of saturated FA and branched-chain FA, higher levels of very long-chain FA, n-3 polyunsaturated FA (PUFA), and monounsaturated FA, with the exception of myristoleic acid. The differences in n-6 PUFA were inconsistent. Gene expression analysis revealed the upregulation of key enzymes controlling de novo FA synthesis, including ACACA, FASN, SCD1, and ELOVL1. In contrast, the expression of genes related to FA transport in the cell and β-oxidation was downregulated. The expression of some genes related to PUFA metabolism was upregulated, while others were downregulated. These results demonstrate a reprogramming of lipid metabolism in EC tissues and suggest potential targets for novel therapeutic interventions in EC. Full article

Opuntia stricta var. dillenii extracts exhibit anti-oxidative and anti-inflammatory properties, which are of significant interest for the prevention and management of metabolic dysfunction-associated fatty liver disease (MAFLD). The present study is the first to investigate the potential anti-steatotic effect of Opuntia stricta var. dillenii extracts. The aim is to evaluate the anti-steatotic effect of extracts from various parts of the plant (whole fruit, peel, pulp, and the industrial by-product, bagasse) in an in vitro model using both murine AML12 and human HepG2 hepatocytes. Results have demonstrated that all tested extracts, including those from the whole fruit, peel, pulp, and bagasse, exert an anti-steatotic effect. In murine hepatocytes, the whole fruit extract at 100 μg/mL and the peel extract at 10 μg/mL presented the highest capacity to reduce PA-induced triglyceride accumulation. In fact, the peel was the most potent extract, preventing lipid accumulation at the lowest dose used. In human HepG2 hepatocytes, the peel, pulp, and bagasse extracts at 100 μg/mL demonstrated the greatest triglyceride reduction, suggesting that the human model is less responsive. Regarding the main mechanism of action, the peel and pulp extracts seem to inhibit de novo lipogenesis. Additionally, the downregulation of the fatty acid transporter CD36 appears to contribute to the prevention of triglyceride accumulation in both extracts. Full article

In this review, we demonstrate that the carotenoids–retinoids–cytochromes c triangle is an important cancer factor controlling most aspects of the development, proliferation, and progression of cancer. Cancer is a multidimensional disease that needs a balance between the enzymes controlling the amount of carotenoids, the production of retinoids (particularly retinoic acid), and the concentration of cytochromes (particularly cytochrome c). The proper balance between these enzymes will help in overcoming the bottleneck in cancer therapeutics using drugs. First, we discuss the impact of carotenoids on cancer. In the next section, we show how carotenoid cleavage products, including retinal, retinol, and retinoic acid, induce positive and negative effects on cancer development. Then, we discuss the impact of cytochrome c on cancer. We have demonstrated that an alteration in the cellular redox status of cytochrome c is a crucial factor in cancer, influencing numerous aspects of malignant progression. The results obtained by Raman imaging showed significant differences between normal and cancerous human cells. First, a significant redox imbalance in the hem group of cytochrome c with the upregulation of the reduced form of hem is observed. Cancer tissue has a higher concentration of reduced cytochrome c than normal tissue. Secondly, both breast and brain tumors exhibit enhanced de novo lipogenesis in comparison to normal cells. Third, this research illustrates the essential function of the extracellular matrix in oxidative phosphorylation and apoptosis pathways. Full article

Hepatic lipogenesis combined with elevated endoplasmic reticulum (ER) stress is central to non-alcoholic steatohepatitis (NASH). However, the therapeutic targeting of key molecules is considerably less accomplished. Adeno-associated virus (AAV)-mediated gene therapies offer a new solution for various human ailments. Comprehensive bio-functional validation studies are essential to assess the impact of AAVs in the target organ for developing both preclinical and clinical gene therapy programs. Here, we have established a robust and efficient protocol for high-titer AAV production to enable detailed Selective ORgan Targeting (SORT) of AAV1, 5, 7, and 8 in vivo. Our results for in vivo SORT showed single organ (liver) targeting by AAV8, no organ targeting by AAV1, and dual organ transduction (liver-brain and liver-VAT) by AAV5 and AAV7. Using a human dataset and preclinical murine models of NASH, we identified an inverse correlation between ER stress-triggered CRELD2 and the de novo lipogenesis driver FASN. Furthermore, liver-specific silencing of CRELD2 via AAV8-shCreld2 strongly supports the contribution of CRELD2 to de novo lipogenesis through FASN regulation. Thus, our study demonstrates a robust method for producing clinically translatable AAVs that could be readily adapted for liver and/or liver-VAT or liver-brain targeted gene therapy. Full article

De novo lipogenesis (DNL) is a metabolic pathway that converts carbohydrates into fatty acids, primarily occurring in the liver and, to a lesser extent, in adipose tissue. While hepatic DNL is highly responsive to dietary carbohydrate intake and regulated by insulin via transcription factors like SREBP-1c, adipose DNL is more modest and less sensitive to dietary overfeeding. Dysregulated DNL contributes to metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). Lifestyle interventions, such as physical exercise, ketogenic diets, and time-restricted eating (TRE) offer promising strategies to regulate DNL and improve metabolic health. Physical exercise enhances glucose uptake in muscles, reduces insulin levels, and promotes lipid oxidation, thereby suppressing hepatic DNL. Endurance and resistance training also improve mitochondrial function, further mitigating hepatic triglyceride accumulation. Ketogenic diets shift energy metabolism toward fatty acid oxidation and ketogenesis, lower insulin, and directly downregulate lipogenic enzyme activity in the liver. TRE aligns feeding with circadian rhythms by optimizing AMP-activated protein kinase (AMPK) activation during fasting periods, which suppresses DNL and enhances lipid metabolism. The combined effects of these interventions demonstrate significant potential for improving lipid profiles, reducing hepatic triglycerides, and preventing lipotoxicity. By addressing the distinct roles of the liver and adipose DNL, these strategies target systemic and localized lipid metabolism dysregulation. Although further research is needed to fully understand their long-term impact, these findings highlight the transformative potential of integrating these approaches into clinical practice to manage metabolic disorders and their associated complications. Full article