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Journal of Translational Medicine Jan 2024Non-alcoholic fatty liver disease (NAFLD) is a liver disorder characterized by the ac-cumulation of fat in hepatocytes without alcohol consumption. Mitochondrial...
BACKGROUND
Non-alcoholic fatty liver disease (NAFLD) is a liver disorder characterized by the ac-cumulation of fat in hepatocytes without alcohol consumption. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play significant roles in NAFLD pathogenesis. The unfolded protein response in mitochondria (UPRmt) is an adaptive mechanism that aims to restore mitochondrial protein homeostasis and mitigate cellular stress. This study aimed to investigate the effects of ( +)-Lipoic acid (ALA) on UPRmt, inflammation, and oxidative stress in an in vitro model of NAFLD using HepG2 cells treated with palmitic acid and oleic acid to induce steatosis.
RESULTS
Treatment with palmitic and oleic acids increased UPRmt-related proteins HSP90 and HSP60 (heat shock protein), and decreased CLPP (caseinolytic protease P), indicating ER stress activation. ALA treatment at 1 μM and 5 μM restored UPRmt-related protein levels. PA:OA (palmitic acid:oleic acid)-induced ER stress markers IRE1α (Inositol requiring enzyme-1), CHOP (C/EBP Homologous Protein), BIP (Binding Immunoglobulin Protein), and BAX (Bcl-2-associated X protein) were significantly reduced by ALA treatment. ALA also enhanced ER-mediated protein glycosylation and reduced oxidative stress, as evidenced by decreased GPX1 (Glutathione peroxidase 1), GSTP1 (glutathione S-transferase pi 1), and GSR (glutathione-disulfide reductase) expression and increased GSH (Glutathione) levels, and improved cellular senescence as shown by the markers β-galactosidase, γH2Ax and Klotho-beta.
CONCLUSIONS
In conclusion, ALA ameliorated ER stress, oxidative stress, and inflammation in HepG2 cells treated with palmitic and oleic acids, potentially offering therapeutic benefits for NAFLD providing a possible biochemical mechanism underlying ALA beneficial effects.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Thioctic Acid; Endoribonucleases; Oleic Acid; Protein Serine-Threonine Kinases; Unfolded Protein Response; Oxidative Stress; Endoplasmic Reticulum Stress; Hepatocytes; Cellular Senescence; Inflammation; Palmitic Acids; Liver; Palmitic Acid
PubMed: 38245790
DOI: 10.1186/s12967-024-04880-x -
Cells May 2024Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer,... (Comparative Study)
Comparative Study Review
Research on retinoid-based cancer prevention, spurred by the effects of vitamin A deficiency on gastric cancer and subsequent clinical studies on digestive tract cancer, unveils novel avenues for chemoprevention. Acyclic retinoids like 4,5-didehydrogeranylgeranoic acid (4,5-didehydroGGA) have emerged as potent agents against hepatocellular carcinoma (HCC), distinct from natural retinoids such as all- retinoic acid (ATRA). Mechanistic studies reveal GGA's unique induction of pyroptosis, a rapid cell death pathway, in HCC cells. GGA triggers mitochondrial superoxide hyperproduction and ER stress responses through Toll-like receptor 4 (TLR4) signaling and modulates autophagy, ultimately activating pyroptotic cell death in HCC cells. Unlike ATRA-induced apoptosis, GGA and palmitic acid (PA) induce pyroptosis, underscoring their distinct mechanisms. While all three fatty acids evoke mitochondrial dysfunction and ER stress responses, GGA and PA inhibit autophagy, leading to incomplete autophagic responses and pyroptosis, whereas ATRA promotes autophagic flux. In vivo experiments demonstrate GGA's potential as an anti-oncometabolite, inducing cell death selectively in tumor cells and thus suppressing liver cancer development. This review provides a comprehensive overview of the molecular mechanisms underlying GGA's anti-HCC effects and underscores its promising role in cancer prevention, highlighting its importance in HCC prevention.
Topics: Humans; Carcinoma, Hepatocellular; Diterpenes; Palmitic Acid; Pyroptosis; Liver Neoplasms; Tretinoin; Animals; Autophagy; Cell Line, Tumor; Endoplasmic Reticulum Stress
PubMed: 38786033
DOI: 10.3390/cells13100809 -
Cell Death & Disease Jul 2022Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic...
Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.
Topics: Animals; Autophagy; Cilia; Diabetes Mellitus, Type 2; Humans; Hypothalamus; Insulin; Insulin Resistance; Mice; Neurons; Palmitic Acid; Pro-Opiomelanocortin
PubMed: 35902579
DOI: 10.1038/s41419-022-05109-9 -
Molecular Neurobiology Aug 2023Chronic intake of a high-fat diet increases saturated fatty acids in the brain causing the progression of neurodegenerative diseases. Palmitic acid is a free fatty acid...
Chronic intake of a high-fat diet increases saturated fatty acids in the brain causing the progression of neurodegenerative diseases. Palmitic acid is a free fatty acid abundant in the diet that at high concentrations may penetrate the blood-brain barrier and stimulate the production of pro-inflammatory cytokines, leading to inflammation in astrocytes. The use of the synthetic neurosteroid tibolone in protection against fatty acid toxicity is emerging, but its transcriptional effects on palmitic acid-induced lipotoxicity remain unclear. Herein, we performed a transcriptome profiling of normal human astrocytes to investigate the molecular mechanisms by which palmitic acid causes cellular damage to astrocytes, and whether tibolone could reverse its detrimental effects. Astrocytes undergo a profound transcriptional change at 2 mM palmitic acid, affecting the expression of 739 genes, 366 upregulated and 373 downregulated. However, tibolone at 10 nM does not entirely reverse palmitic acid effects. Additionally, the protein-protein interaction reveals two novel gene clustering modules. The first module involves astrocyte defense responses by upregulation of pathways associated with antiviral innate immunity, and the second is linked to lipid metabolism. Our data suggest that activation of viral response signaling pathways might be so far, the initial molecular mechanism of astrocytes in response to a lipotoxic insult by palmitic acid, triggered particularly upon increased expression levels of IFIT2, IRF1, and XAF1. Therefore, this novel approach using a global gene expression analysis may shed light on the pleiotropic effects of palmitic acid on astrocytes, and provide a basis for future studies addressed to elucidate these responses in neurodegenerative conditions, which is highly valuable for the design of therapeutic strategies.
Topics: Humans; Palmitic Acid; Antiviral Agents; Astrocytes; Interferon Type I; Fatty Acids; Cholesterol
PubMed: 37184765
DOI: 10.1007/s12035-023-03366-z -
Cellular and Molecular Life Sciences :... Jul 2019Emerging evidence shows that palmitic acid (PA), a common fatty acid in the human diet, serves as a signaling molecule regulating the progression and development of many... (Review)
Review
Emerging evidence shows that palmitic acid (PA), a common fatty acid in the human diet, serves as a signaling molecule regulating the progression and development of many diseases at the molecular level. In this review, we focus on its regulatory roles in the development of five pathological conditions, namely, metabolic syndrome, cardiovascular diseases, cancer, neurodegenerative diseases, and inflammation. We summarize the clinical and epidemiological studies; and also the mechanistic studies which have identified the molecular targets for PA in these pathological conditions. Activation or inactivation of these molecular targets by PA controls disease development. Therefore, identifying the specific targets and signaling pathways that are regulated by PA can give us a better understanding of how these diseases develop for the design of effective targeted therapeutics.
Topics: Animals; Autophagy; Cardiovascular Diseases; Humans; Inflammation; Metabolic Syndrome; Neoplasms; Neurodegenerative Diseases; Palmitic Acid; Signal Transduction
PubMed: 30968170
DOI: 10.1007/s00018-019-03092-7 -
Biochimica Et Biophysica Acta.... Jun 2023Cholangiocarcinoma (CCA), a cancer of the biliary tract, is a significant health problem in Thailand. Reprogramming of cellular metabolism and upregulation of lipogenic...
Cholangiocarcinoma (CCA), a cancer of the biliary tract, is a significant health problem in Thailand. Reprogramming of cellular metabolism and upregulation of lipogenic enzymes have been revealed in CCA, but the mechanism is unclear. The current study highlighted the importance of acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme in de novo lipogenesis, on CCA migration. ACC1 expression in human CCA tissues was determined by immunohistochemistry. The results demonstrated that increased ACC1 was related to the shorter survival of CCA patients. Herein, ACC1-deficient cell lines (ACC1-KD) were generated by the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (cas9) system and were used for the comparative study. The ACC1 levels in ACC1-KD were 80-90 % lower than in parental cells. Suppression of ACC1 significantly reduced intracellular malonyl-CoA and neutral lipid contents. Two-fold growth retardation and 60-80 % reduced CCA cell migration and invasion were observed in ACC1-KD cells. The reduced 20-40 % of intracellular ATP levels, AMPK activation, lowered NF-κB p65 nuclear translocation, and snail expression were emphasized. Migration of ACC1-KD cells was restored by supplementation with palmitic acid and malonyl-CoA. Altogether, the importance of rate-limiting enzyme in de novo fatty acid synthesis, ACC1, and AMPK-NF-κB-snail axis on CCA progression was suggested herein. These might be the novel targets for CCA drug design. (ACC1, AMPK, Cholangiocarcinoma, De novo lipogenesis, NF-κB, Palmitic acid).
Topics: Humans; Acetyl-CoA Carboxylase; AMP-Activated Protein Kinases; Cholangiocarcinoma; NF-kappa B; Palmitic Acid; Snail Family Transcription Factors
PubMed: 36972768
DOI: 10.1016/j.bbadis.2023.166694 -
International Journal of Molecular... Mar 2023Sarcopenia associated with aging and obesity is characterized by the atrophy of fast-twitch muscle fibers and an increase in intramuscular fat deposits. However, the...
Sarcopenia associated with aging and obesity is characterized by the atrophy of fast-twitch muscle fibers and an increase in intramuscular fat deposits. However, the mechanism of fast-twitch fiber-specific atrophy remains unclear. In this study, we aimed to assess the effect of palmitic acid (PA), the most common fatty acid component of human fat, on muscle fiber type, focusing on the expression of fiber-type-specific myosin heavy chain (MHC). Myotubes differentiated from C2C12 myoblasts were treated with PA. The PA treatment inhibited myotube formation and hypertrophy while reducing the gene expression of MHC IIb and IIx, specific isoforms of fast-twitch fibers. Consistent with this, a significant suppression of MHC IIb protein expression in PA-treated cells was observed. A reporter assay using plasmids containing the MHC IIb gene promoter revealed that the PA-induced reduction in MHC IIb gene expression was caused by the suppression of MyoD transcriptional activity through its phosphorylation. Treatment with a specific protein kinase C (PKC) inhibitor recovered the reduction in MHC IIb gene expression levels in PA-treated cells, suggesting the involvement of the PA-induced activation of PKC. Thus, PA selectively suppresses the mRNA and protein expression of fast-twitch MHC by modulating MyoD activity. This finding provides a potential pathogenic mechanism for age-related sarcopenia.
Topics: Humans; Muscle Fibers, Skeletal; Muscle, Skeletal; Myosin Heavy Chains; Palmitic Acid; Phosphorylation; Sarcopenia; Animals; Mice; MyoD Protein
PubMed: 36982919
DOI: 10.3390/ijms24065847 -
Biochimica Et Biophysica Acta.... Feb 2020The mechanisms leading to the low-grade inflammation observed during obesity are not fully understood. Seeking the initiating events, we tested the hypothesis that the...
The mechanisms leading to the low-grade inflammation observed during obesity are not fully understood. Seeking the initiating events, we tested the hypothesis that the intestine could be damaged by repeated lipid supply and therefore participate in inflammation. In mice, 1-5 palm oil gavages increased intestinal permeability via decreased expression and mislocalization of junctional proteins at the cell-cell contacts; altered the intestinal bacterial species by decreasing the abundance of Akkermansia muciniphila, segmented filamentous bacteria, and Clostridium leptum; and increased inflammatory cytokine expression. This was further studied in human intestinal epithelial Caco-2/TC7 cells using the two main components of palm oil, i.e., palmitic and oleic acid. Saturated palmitic acid impaired paracellular permeability and junctional protein localization, and induced inflammatory cytokine expression in the cells, but unsaturated oleic acid did not. Inhibiting de novo ceramide synthesis prevented part of these effects. Altogether, our data show that short exposure to palm oil or palmitic acid induces intestinal dysfunctions targeting barrier integrity and inflammation. Excessive palm oil consumption could be an early player in the gut alterations observed in metabolic diseases.
Topics: Administration, Oral; Animals; Caco-2 Cells; Cytokines; Disease Models, Animal; Endoplasmic Reticulum Stress; Feces; Gastrointestinal Microbiome; Humans; Inflammation Mediators; Intestinal Mucosa; Male; Metabolic Syndrome; Mice; Palm Oil; Palmitic Acid; Permeability; Tight Junctions
PubMed: 31647994
DOI: 10.1016/j.bbalip.2019.158530 -
Arteriosclerosis, Thrombosis, and... Jul 2023Obesity and diabetes are associated with elevated free fatty acids like palmitic acid (PA), which promote chronic inflammation and impaired inflammation resolution...
BACKGROUND
Obesity and diabetes are associated with elevated free fatty acids like palmitic acid (PA), which promote chronic inflammation and impaired inflammation resolution associated with cardiometabolic disorders. Long noncoding RNAs (lncRNAs) are implicated in inflammatory processes; however, their roles in PA-regulated inflammation and resolution are unclear.
METHODS
We performed RNA-sequencing analysis to identify PA-regulated coding genes and novel lncRNAs in CD14 monocytes from healthy volunteers. We investigated the regulation and function of an uncharacterized PA-induced lncRNA (PA-egulated nti-nflammatory ncRNA). We examined its role in inflammation resolution by employing knockdown and overexpression strategies in human and mouse macrophages. We also used RNA pulldown coupled with mass spectrometry to identify interacting nuclear proteins and their mechanistic involvement in functions in human macrophages.
RESULTS
Treatment of human CD14 monocytes with PA-induced several lncRNAs and genes associated with inflammatory phenotype. PA strongly induced lncRNA expressed near . was also induced by cytokines and infectious agents in human monocytes/macrophages and was regulated by NF-κB (nuclear factor-kappa B). Time course studies showed was induced during inflammation resolution phase in PA-treated macrophages. knockdown with antisense oligonucleotides upregulated key inflammatory genes and vice versa with overexpression. We found that interacts with ELAVL1 (ELAV-like RNA-binding protein 1) protein via adenylate/uridylate-rich elements (AU-rich elements; AREs). ELAVL1 knockdown inhibited the anti-inflammatory functions of . Moreover, knockdown increased cytosolic localization of ELAVL1 and increased the stability of ARE-containing inflammatory genes. Mouse orthologous was downregulated in macrophages from mice with diabetes and atherosclerosis. overexpression attenuated proinflammatory genes in mouse macrophages.
CONCLUSIONS
Upregulation of under acute inflammatory conditions contributes to proresolution mechanisms via -ELAVL1 interactions. Conversely, downregulation in cardiometabolic diseases enhances ELAVL1 function and impairs inflammation resolution to further augment inflammation. Thus, inflammation-resolving lncRNAs like represent novel targets to combat inflammatory cardiometabolic diseases.
Topics: Humans; Mice; Animals; Monocytes; RNA, Long Noncoding; Palmitic Acid; Macrophages; Inflammation; NF-kappa B; Atherosclerosis; RNA-Binding Proteins; ELAV-Like Protein 1
PubMed: 37128912
DOI: 10.1161/ATVBAHA.122.318536 -
The FEBS Journal Dec 2021Protein cysteine palmitoylation, or S-palmitoylation, has been known for about 40 years, and thousands of proteins in humans are known to be modified. Because of the... (Review)
Review
Protein cysteine palmitoylation, or S-palmitoylation, has been known for about 40 years, and thousands of proteins in humans are known to be modified. Because of the large number of proteins modified, the importance and physiological functions of S-palmitoylation are enormous. However, most of the known physiological functions of S-palmitoylation can be broadly classified into two categories, neurological or immunological. This review provides a summary on the function of S-palmitoylation from the immunological perspective. Several important immune signaling pathways are discussed, including STING, NOD1/2, JAK-STAT in cytokine signaling, T-cell receptor signaling, chemotactic GPCR signaling, apoptosis, phagocytosis, and endothelial and epithelial integrity. This review is not meant to be comprehensive, but rather focuses on specific examples to highlight the versatility of palmitoylation in regulating immune signaling, as well as the potential and challenges of targeting palmitoylation to treat immune diseases.
Topics: Animals; Cysteine; Cytokines; Humans; Inflammation; Palmitic Acid; Signal Transduction
PubMed: 33506611
DOI: 10.1111/febs.15728