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The EMBO Journal Dec 2023Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of morbidity with limited treatment options. Thus, accurate in vitro systems to test...
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing cause of morbidity with limited treatment options. Thus, accurate in vitro systems to test new therapies are indispensable. While recently, human liver organoid models have emerged to assess steatotic liver disease, a systematic evaluation of their translational potential is still missing. Here, we evaluated human liver organoid models of MASLD, comparatively testing disease induction in three conditions: oleic acid, palmitic acid, and TGF-β1. Through single-cell analyses, we find that all three models induce inflammatory signatures, but only TGF-β1 promotes collagen production, fibrosis, and hepatic stellate cell expansion. In striking contrast, oleic acid ameliorates fibrotic signatures and reduces the hepatic stellate cell population. Linking data from each model to gene expression signatures associated with MASLD disease progression further demonstrates that palmitic acid and TGF-β1 more robustly model inflammation and fibrosis. Our findings highlight the importance of stratifying MASLD organoid models by signatures of clinical disease progression, provide a single-cell reference to benchmark future organoid injury models, and allow us to study evolving steatohepatitis, fibrosis, and HSC susceptibility to injury in a dynamic, multi-lineage human in vitro system.
Topics: Humans; Liver Cirrhosis; Transforming Growth Factor beta1; Fatty Liver; Gene Expression Profiling; Disease Progression
PubMed: 37962490
DOI: 10.15252/embj.2023113898 -
Research (Washington, D.C.) 2023Non-alcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), is a leading cause of cirrhosis and liver cancer worldwide; nevertheless, there are no...
Non-alcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), is a leading cause of cirrhosis and liver cancer worldwide; nevertheless, there are no Food and Drug Administration-approved drugs for treating NASH until now. Peroxisome proliferator-activated receptor alpha (PPARα) is an interesting therapeutic target for treating metabolic disorders in the clinic, including NASH. Herpetrione, a natural lignan compound isolated from Tibetan medicine , exerts various hepatoprotective effects, but its efficacy and molecular mechanism in treating NASH have not yet been elucidated. Here, we discovered that herpetrione lessened lipid accumulation and inflammation in hepatocytes stimulated with oleic acid and lipopolysaccharide, and effectively alleviated NASH caused by a high-fat diet or methionine-choline-deficient diet by regulating glucolipid metabolism, insulin resistance, and inflammation. Mechanistically, RNA-sequencing analyses further showed that herpetrione activated PPAR signaling, which was validated by protein expression. Furthermore, the analysis of molecular interactions illustrated that herpetrione bound directly to the PPARα protein, with binding sites extending to the Arm III domain. PPARα deficiency also abrogated the protective effects of herpetrione against NASH, suggesting that herpetrione protects against hepatic steatosis and inflammation by activation of PPARα signaling, thereby alleviating NASH. Our findings shed light on the efficacy of a natural product for treating NASH, as well as the broader prospects for NASH treatment by targeting PPARα.
PubMed: 38034083
DOI: 10.34133/research.0276 -
Autophagy Oct 2023Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly, and there is currently no clinical treatment targeting the...
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among the elderly, and there is currently no clinical treatment targeting the primary impairment of AMD. The earliest clinical hallmark of AMD is drusen, which are yellowish spots mainly composed of lipid droplets (LDs) accumulated under the retinal pigment epithelium (RPE). However, the potential pathogenic role of this excessive LD accumulation in AMD is yet to be determined, partially due to a lack of chemical tools to manipulate LDs specifically. Here, we employed our recently developed Lipid Droplets·AuTophagy Tethering Compounds (LD∙ATTECs) to degrade LDs and to evaluate its consequence on the AMD-like phenotypes in apoe (apolipoprotein E; B6/JGpt-Apoe/Gpt) mouse model. apoe mice fed with high-fat diet (apoe-HFD) exhibited excessive LD accumulation in the retina, particularly with AMD-like phenotypes including RPE degeneration, Bruch's membrane (BrM) thickening, drusen-like deposits, and photoreceptor dysfunction. LD·ATTEC treatment significantly cleared LDs in RPE/choroidal tissues without perturbing lipid synthesis-related proteins and rescued RPE degeneration and photoreceptor dysfunction in apoe-HFD mice. This observation implied a causal relationship between LD accumulation and AMD-relevant phenotypes. Mechanically, the apoe-HFD mice exhibited elevated oxidative stress and inflammatory signals, both of which were mitigated by the LD·ATTEC treatment. Collectively, this study demonstrated that LD accumulation was a trigger for the process of AMD and provided entry points for the treatment of the initial insult of AMD by degrading LDs. AMD: age-related macular degeneration; : apolipoprotein E; ATTECs: autophagy-tethering compounds; BODIPY: boron-dipyrromethene; BrM: Bruch's membrane; ERG: electroretinogram; HFD: high-fat diet; LD·ATTECs: Lipid Droplets·AuTophagy Tethering Compounds; LDs: lipid droplets; OA: oleic acid; OPL: outer plexiform layer; ROS: reactive oxygen species; RPE: retinal pigment epithelium.
Topics: Mice; Animals; Lipid Droplets; Autophagy; Macular Degeneration; Retinal Pigment Epithelium; Apolipoproteins E; Phenotype; Apolipoproteins
PubMed: 37266932
DOI: 10.1080/15548627.2023.2220540 -
Nutrients Aug 2023The Mediterranean diet is a healthy dietary pattern whose main characteristic is olive oil consumption. The potential health benefits of olive oil have been extensively... (Review)
Review
The Mediterranean diet is a healthy dietary pattern whose main characteristic is olive oil consumption. The potential health benefits of olive oil have been extensively investigated and the present review provides the more recent clinical evidence supporting the positive impact of olive oil intake on human health. PubMed ( = 227) and Scopus ( = 308) databases were searched for published clinical studies in English over the past six years (October 2016 to December 2022), following key word searches of "olive oil" and "health". Major findings associated olive oil with antioxidant and anti-inflammatory effects, improvement in endothelial function and lipid profile, prevention of obesity, diabetes, cardiovascular and neurodegenerative diseases, and modulation of the gut microbiota. These benefits are attributed to the nutritional composition of olive oil, which has a high content of monounsaturated fatty acids (MUFA) (oleic acid in particular) and minor compounds such as polyphenols (oleuropein and hydroxytyrosol). Although additional research continues to be required, the more recently generated evidence supports the potential of olive oil to contribute beneficially to health and to the prevention and management of a variety of non-communicable diseases, as a consequence of the synergism between its components' complexity.
Topics: Humans; Antioxidants; Databases, Factual; Diet, Mediterranean; Fatty Acids, Monounsaturated; Gastrointestinal Microbiome; Olive Oil
PubMed: 37630815
DOI: 10.3390/nu15163625 -
Cancers Nov 2023Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and...
Reprogramming of fatty acid metabolism promotes cell growth and metastasis through a variety of processes that stimulate signaling molecules, energy storage, and membrane biosynthesis in endometrial cancer. Oleic acid is one of the most important monounsaturated fatty acids in the human body, which appears to have both pro- and anti-tumorigenic activities in various pre-clinical models. In this study, we evaluated the potential anti-tumor effects of oleic acid in endometrial cancer cells and the mouse model of endometrial cancer. Oleic acid increased lipogenesis, inhibited cell proliferation, caused cell cycle G1 arrest, induced cellular stress and apoptosis, and suppressed invasion in endometrial cancer cells. Targeting of diacylglycerol acyltransferases 1 and 2 effectively increased the cytotoxicity of oleic acid. Moreover, oleic acid significantly increased the expression of wild-type PTEN, and knockdown of PTEN by shRNA partially reversed the anti-proliferative and anti-invasive effects of oleic acid. Inhibition of the AKT/mTOR pathway by ipatasertib effectively increased the anti-tumor activity of oleic acid in endometrial cancer cells. Oleic acid treatment (10 mg/kg, daily, oral) for four weeks significantly inhibited tumor growth by 52.1% in the mice. Our findings demonstrated that oleic acid exhibited anti-tumorigenic activities, dependent on the PTEN/AKT/mTOR signaling pathway, in endometrial cancer.
PubMed: 38001668
DOI: 10.3390/cancers15225407 -
Chemical Senses Jan 2024Although studies have shown that olfaction may contribute to the perception of tastant, literature is scarce or circumstantial, especially in humans. This study aims to...
Although studies have shown that olfaction may contribute to the perception of tastant, literature is scarce or circumstantial, especially in humans. This study aims to (i) explore whether humans can perceive solutions of basic prototypical tastants through orthonasal and retronasal olfaction and (ii) to examine what volatile odor compounds (VOCs) underlie this ability. Solutions of 5 basic tastants (sucrose, sodium chloride, citric acid, monosodium glutamate [MSG], quinine) dissolved in water, and 2 fatty acids (oleic and linoleic acid) dissolved in mineral oil were prepared. Triangle discrimination tests were performed (n = 41 in duplicate) to assess whether the tastant solutions can be distinguished from blanks (solvents) through ortho- and retronasal olfaction. Participants were able to distinguish all tastant solutions from blank through orthonasal olfaction. Only sucrose, sodium chloride, oleic acid, and linoleic acid were distinguished from blank by retronasal olfaction. Ethyl dichloroacetate, methylene chloride, and/or acetone were identified in the headspace of sucrose, MSG, and quinine solutions but not in the headspace of water, sodium chloride, and citric acid solutions. Fat oxidation compounds such as alcohols and aldehydes were detected in the headspace of the oleic and linoleic acid solutions but not the mineral oil. We conclude that prototypical tastant solutions can be discriminated from water and fatty acid solutions from mineral oil through orthonasal olfaction. Differences in the volatile headspace composition between blanks and tastant solutions may have facilitated the olfactory discrimination. These findings can have methodological implications for future studies assessing gustatory perception using these prototypical taste compounds.
Topics: Humans; Smell; Sodium Chloride; Sodium Glutamate; Quinine; Mineral Oil; Taste; Water; Sucrose; Citric Acid; Linoleic Acids
PubMed: 38175732
DOI: 10.1093/chemse/bjad054 -
Theranostics 2023Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy. Understanding...
Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy. Understanding the molecular mechanisms regulating anti-EGFR-resistant CRC metastasis can improve CRC therapy. This study aimed to investigate the effects of IL-8 and the activation of KRAS on reactive oxygen species (ROS) production and metastasis of hyperlipidemia-associated CRC harboring mutations of KRAS and p53. The cytokine array analysis determined the up-expression of secreted factors, including IL-8. The clinical relevance of the relationship between IL-8 and angiopoietin-like 4 (ANGPTL4) was examined in CRC patients from National Cheng Kung University Hospital and TCGA dataset. Expressions of IL-8, ANGPTL4, NADPH oxidase 4 (NOX4), and epithelial-mesenchymal transition (EMT) markers in free fatty acids (FFAs)-treated KRAS/p53 mutant CRC cells were determined. The hyperlipidemia-triggered metastatic ability of CRC cells under treatments of antioxidants, statin, and cetuximab or knockdown of IL-8, KRAS, and EGFR was evaluated in vitro and in vivo. In addition, the effects of antioxidants and depletion of IL-8 and KRAS on the correlation between ROS production and hyperlipidemia-promoted CRC metastasis were also clarified. In this study, we found that free fatty acids promoted KRAS/p53-mutant but not single-mutant or non-mutant CRC cell metastasis. IL-8, the most abundant secreted factor in KRAS/p53-mutant cells, was correlated with the upregulation of NOX4 expression and ROS production under oleic acid (OA)-treated conditions. In addition, the metastasis of KRAS/p53-mutant CRC relies on the ANGPTL4/IL-8/NOX4 axis and the activation of KRAS. The antioxidants and inactivation of KRAS also inhibited OA-induced EMT and metastasis. Although KRAS mediated EGF- and OA-promoted CRC cell invasion, the inhibition of EGFR did not affect OA-induced ANGPTL4/IL-8/NOX4 axis and CRC metastasis. The high-fat diet mice fed with vitamin E and statin or in IL-8-depleted cells significantly inhibited tumor extravasation and metastatic lung growth of CRC. The antioxidants, statins, and targeting IL-8 may provide better outcomes for treating metastatic CRC that harbors multigene mutations and anti-EGFR resistance.
Topics: Animals; Mice; Antibodies; Antioxidants; Colonic Neoplasms; Fatty Acids, Nonesterified; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-8; Oleic Acids; Proto-Oncogene Proteins p21(ras); Reactive Oxygen Species; Tumor Suppressor Protein p53; Humans
PubMed: 37649607
DOI: 10.7150/thno.85855 -
Cell Communication and Signaling : CCS Oct 2023Abnormal platelet activation is a key factor in the occurrence and development of thrombotic diseases. However, the physiological mechanisms that underlie platelet...
BACKGROUND
Abnormal platelet activation is a key factor in the occurrence and development of thrombotic diseases. However, the physiological mechanisms that underlie platelet homeostasis remain unclear. Oleic acid, one of the most abundant lipids in the human diet, has potential antithrombotic effects. This study aimed to investigate the effects of oleic acid on platelet activation and thrombosis.
METHODS
Platelet aggregation, ATP release, and fibrinogen spread were evaluated to determine the role of oleic acid in platelet activation. A ferric chloride-induced carotid injury model was used to establish the effect of oleic acid on thrombus formation in vivo. Western blotting analysis and transfection experiments were performed to determine the mechanisms involved in this process.
RESULTS
Oleic acid inhibited platelet aggregation, granule release, and calcium mobilization. Furthermore, it inhibited the spread of platelets on fibrinogen. We also found that oleic acid delayed arterial thrombosis in mice, as demonstrated in a murine model of ferric chloride-induced carotid artery thrombosis. The molecular mechanism of its inhibition of platelet activity may be through the Syk-PLCγ2 and CaMKKβ/AMPKα/VASP pathways. In addition, we demonstrated that the phosphorylation of AMPK at Ser496 was an important mechanism of platelet activation.
CONCLUSIONS
Our study showed that oleic acid inhibits platelet activation and reduces thrombogenesis by inhibiting the phosphorylation of multiple signaling molecules, offering new insights into the research and development of antiplatelet drugs. Video Abstract.
Topics: Humans; Mice; Animals; Oleic Acid; Platelet Activation; Blood Platelets; Thrombosis; Phosphorylation; Collagen; Fibrinogen
PubMed: 37817162
DOI: 10.1186/s12964-023-01276-0 -
Frontiers in Nutrition 2023The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is on the rise globally. It is currently one of the most prevalent liver diseases and one... (Review)
Review
The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) is on the rise globally. It is currently one of the most prevalent liver diseases and one of the world's important public health problems. At present, there is no consensus on a pharmacological treatment for MAFLD. By contrast, lifestyle interventions based on exercise and a balanced diet are considered to be the cornerstone of MAFLD management. Mediterranean diet (MD) have a large content of polyphenols, polyunsaturated fatty acids, oleic acid, carotenoids and fiber, which carry out antioxidant, anti-inflammatory and antibacterial benefits. It has been considered to reduce the incidence rate of cardiovascular disease and type 2 diabetes. The purpose of this narrative review is therefore to summarize and analyze the evidence for the effect of MD on metabolic outcomes in MAFLD patients.
PubMed: 37899839
DOI: 10.3389/fnut.2023.1225946