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Cellular and Molecular Gastroenterology... 2022The prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no...
BACKGROUND & AIMS
The prevalence of nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions globally as a result of the rapid increase in obesity. However, there is no Food and Drug Administration-approved pharmacotherapy available for NAFLD. This study investigated the role of autotaxin, a secreted enzyme that hydrolyzes lysophosphatidylcholine to produce lysophosphatidic acid (LPA), in the pathogenesis of NAFLD and to explore whether genetic or pharmacologic interventions targeting autotaxin ameliorate NAFLD.
METHODS
The clinical association of autotaxin with the severity of NAFLD was analyzed in 125 liver biopsy-proven NAFLD patients. C57BL/6N mice or fibroblast growth factor 21 (FGF21)-null mice were fed a high-fat diet or a choline-deficient diet to investigate the role of the autotaxin-FGF21 axis in NAFLD development by hepatic knockdown and antibody neutralization. Huh7 cells were used to investigate the autocrine effects of autotaxin.
RESULTS
Serum autotaxin levels were associated positively with histologic scores and NAFLD severity. Hepatocytes, but not adipocytes, were the major contributor to increased circulating autotaxin in both patients and mouse models with NAFLD. In mice, knocking-down hepatic autotaxin or treatment with a neutralizing antibody against autotaxin significantly reduced high-fat diet-induced NAFLD and high fat- and choline-deficient diet-induced nonalcoholic steatohepatitis and fibrosis, accompanied by a marked increase of serum FGF21. Mechanistically, autotaxin inhibited the transcriptional activity of peroxisome proliferator-activated receptor α through LPA-induced activation of extracellular signal-regulated kinas, thereby leading to suppression of hepatic FGF21 production. The therapeutic benefit of anti-autotaxin neutralizing antibody against NAFLD was abrogated in FGF21-null mice.
CONCLUSIONS
Liver-secreted autotaxin acts in an autocrine manner to exacerbate NAFLD through LPA-induced suppression of the peroxisome proliferator-activated receptor α-FGF21 axis and is a promising therapeutic target for NAFLD.
Topics: Animals; Mice; Antibodies, Neutralizing; Choline; Diet, High-Fat; Hepatocytes; Lysophosphatidylcholines; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; PPAR alpha; Phosphoric Diester Hydrolases
PubMed: 35931383
DOI: 10.1016/j.jcmgh.2022.07.012 -
Cells Dec 2022Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Mechanistic investigations into sepsis have mainly focused on targeting...
Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Mechanistic investigations into sepsis have mainly focused on targeting inflammatory pathways; however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulations that take place in sepsis might uncover novel therapeutic opportunities. The role of peroxisome proliferator-activated receptor alpha (PPARɑ) in liver dysfunction during sepsis has recently been described, and restoring PPARɑ signaling has proven to be successful in mouse polymicrobial sepsis. To confirm that such therapy might be translated to septic patients, we analyzed metabolic perturbations in the liver of a porcine fecal peritonitis model. Resuscitation with fluids, vasopressor, antimicrobial therapy and abdominal lavage were applied to the pigs in order to mimic human clinical care. By using RNA-seq, we detected downregulated PPARɑ signaling in the livers of septic pigs and that reduced PPARɑ levels correlated well with disease severity. As PPARɑ regulates the expression of many genes involved in fatty acid oxidation, the reduced expression of these target genes, concomitant with increased free fatty acids in plasma and ectopic lipid deposition in the liver, was observed. The results obtained with pigs are in agreement with earlier observations seen in mice and support the potential of targeting defective PPARɑ signaling in clinical research.
Topics: Humans; Animals; Mice; Swine; PPAR alpha; Shock, Septic; Sepsis; Liver Diseases
PubMed: 36552845
DOI: 10.3390/cells11244080 -
International Journal of Cancer Apr 2023The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that...
The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH ) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH , but not at acidic pH . Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.
Topics: Humans; Transcription Factors; Gene Expression Regulation; PPAR alpha; Fatty Acids; Neoplasms; Acidosis; Lipid Metabolism; Liver; Tumor Microenvironment
PubMed: 36533672
DOI: 10.1002/ijc.34404 -
Nutrition, Metabolism, and... Jul 2023Recently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study...
BACKGROUND AND AIMS
Recently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study were to evaluate the efficacy and safety of pemafibrate in hypertriglyceridemia patients under clinical settings.
METHODS AND RESULTS
We evaluated changes in lipid profiles and various parameters before and after 24-week pemafibrate administration in patients with hypertriglyceridemia who had not previously taken fibrate medications. There were 79 cases included in the analysis. 24 weeks after the treatment with pemafibrate, TG was significantly reduced from 312 ± 226 to 167 ± 94 mg/dL. In addition, lipoprotein fractionation tests using PAGE method showed a significant decrease in the ratio of VLDL and remnant fractionations, which are TG-rich lipoproteins. After pemafibrate administration, body weight, HbA1c, eGFR, and CK levels were not changed, but liver injury indices such as ALT, AST, and γ-GTP were significantly improved.
CONCLUSION
In this study, pemafibrate improved the metabolism of atherosclerosis-induced lipoproteins in hypertriglyceridemia patients. In addition, it showed no off-target effects such as hepatic and renal damage or rhabdomyolysis.
Topics: Humans; Retrospective Studies; Hypertriglyceridemia; PPAR alpha; Benzoxazoles; Triglycerides
PubMed: 37246074
DOI: 10.1016/j.numecd.2023.02.011 -
Cell Death & Disease Feb 2018Among metabolic rearrangements occurring in cancer cells, lipid metabolism alteration has become a hallmark, aimed at sustaining accelerated proliferation. In... (Review)
Review
Among metabolic rearrangements occurring in cancer cells, lipid metabolism alteration has become a hallmark, aimed at sustaining accelerated proliferation. In particular, fatty acids (FAs) are dramatically required by cancer cells as signalling molecules and membrane building blocks, beyond bioenergetics. Along with de novo biosynthesis, free FAs derive from dietary sources or from intracellular lipid droplets, which represent the storage of triacylglycerols (TAGs). Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme of lipolysis, catalysing the first step of intracellular TAGs hydrolysis in several tissues. However, the roles of ATGL in cancer are still neglected though a putative tumour suppressor function of ATGL has been envisaged, as its expression is frequently reduced in different human cancers (e.g., lung, muscle, and pancreas). In this review, we will introduce lipid metabolism focusing on ATGL functions and regulation in normal cell physiology providing also speculative perspectives on potential non-energetic functions of ATGL in cancer. In particular, we will discuss how ATGL is implicated, mainly through the peroxisome proliferator-activated receptor-α (PPAR-α) signalling, in inflammation, redox homoeostasis and autophagy, which are well-known processes deregulated during cancer formation and/or progression.
Topics: Animals; Energy Metabolism; Humans; Lipase; Neoplasms; PPAR alpha; Signal Transduction; Triglycerides
PubMed: 29472527
DOI: 10.1038/s41419-018-0345-z -
American Journal of Physiology. Heart... Jun 2005The transcription of key metabolic regulatory enzymes in the heart is altered in the diabetic state, yet little is known of the underlying mechanisms. The aim of this...
The transcription of key metabolic regulatory enzymes in the heart is altered in the diabetic state, yet little is known of the underlying mechanisms. The aim of this study was to investigate the role of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in modulating cardiac insulin-sensitive glucose transporter (GLUT-4) protein levels in altered metabolic states and to determine the functional consequences by assessing cardiac ischemic tolerance. Wild-type and PPAR-alpha-null mouse hearts were isolated and perfused 6 wk after streptozotocin administration or after 14 mo on a high-fat diet or after a 24-h fast. Myocardial d-[2-(3)H]glucose uptake was measured during low-flow ischemia, and differences in GLUT-4 protein levels were quantified using Western blotting. In wild-type mice in all three metabolic states, elevated plasma free fatty acids were associated with lower total cardiac GLUT-4 protein levels and decreased glucose uptake during ischemia, resulting in poor postischemic functional recovery. Although PPAR-alpha-null mice also had elevated plasma free fatty acids, they had neither decreased cardiac GLUT-4 levels nor decreased glucose uptake during ischemia and, consequently, did not have poor recovery during reperfusion. We conclude that elevated plasma free fatty acids are associated with increased injury during ischemia due to decreased cardiac glucose uptake resulting from lower cardiac GLUT-4 protein levels, the levels of GLUT-4 being regulated, probably indirectly, through PPAR-alpha activation.
Topics: Animals; Biological Transport; Blood Pressure; Cholesterol; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Disease Susceptibility; Fatty Acids, Nonesterified; Glucose; Heart Rate; Insulin; Mice; Mice, Knockout; Myocardial Ischemia; PPAR alpha
PubMed: 15665064
DOI: 10.1152/ajpheart.00200.2004 -
Journal of Biochemistry Apr 2023HNF4α regulates various genes to maintain liver function. There have been reports linking HNF4α expression to the development of non-alcoholic fatty liver disease...
HNF4α regulates various genes to maintain liver function. There have been reports linking HNF4α expression to the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. In this study, liver-specific Hnf4a-deficient mice (Hnf4aΔHep mice) developed hepatosteatosis and liver fibrosis, and they were found to have difficulty utilizing glucose. In Hnf4aΔHep mice, the expression of fatty acid oxidation-related genes, which are PPARα target genes, was increased in contrast to the decreased expression of PPARα, suggesting that Hnf4aΔHep mice take up more lipids in the liver instead of glucose. Furthermore, Hnf4aΔHep/Ppara-/- mice, which are simultaneously deficient in HNF4α and PPARα, showed improved hepatosteatosis and fibrosis. Increased C18:1 and C18:1/C18:0 ratio was observed in the livers of Hnf4aΔHep mice, and the transactivation of PPARα target gene was induced by C18:1. When the C18:1/C18:0 ratio was close to that of Hnf4aΔHep mouse liver, a significant increase in transactivation was observed. In addition, the expression of Pgc1a, a coactivator of PPARs, was increased, suggesting that elevated C18:1 and Pgc1a expression could contribute to PPARα activation in Hnf4aΔHep mice. These insights may contribute to the development of new diagnostic and therapeutic approaches for NAFLD by focusing on the HNF4α and PPARα signaling cascade.
Topics: Animals; Mice; Hepatocyte Nuclear Factor 4; Lipid Metabolism; Liver; Liver Cirrhosis; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; PPAR alpha
PubMed: 36779417
DOI: 10.1093/jb/mvad005 -
Journal of Nutritional Science and... Aug 2008It is reported that arachidonic acid strongly induces the conformational change in vitro and transactivity of PPAR alpha in colorectal cancer cell line Caco-2. In this...
It is reported that arachidonic acid strongly induces the conformational change in vitro and transactivity of PPAR alpha in colorectal cancer cell line Caco-2. In this study, we demonstrated that the induction of conformational change and transactivity of PPAR delta by arachidonic acid, as well as other polyunsaturated fatty acids, was considerably lower than that of PPAR alpha. Mammalian two-hybrid assay showed that arachidonic acid enhanced binding of one of the coactivators, p300, to PPAR alpha but not to PPAR delta. Additionally, arachidonic acid induced in vitro binding of both PPAR alpha-RXR alpha and PPAR delta-RXR alpha heterodimers to several PPREs on CRBPII, L-FABP and ACO genes. Our results suggest that the lower transactivity of PPAR delta for arachidonic acid in Caco-2 cells, compared with PPAR alpha, is associated with the binding activity of p300 to the receptor.
Topics: Arachidonic Acid; Caco-2 Cells; E1A-Associated p300 Protein; Genes, Reporter; Humans; Linoleic Acid; PPAR alpha; PPAR delta; Protein Binding; Protein Conformation; Transfection; Two-Hybrid System Techniques
PubMed: 18797151
DOI: 10.3177/jnsv.54.298 -
Biochimica Et Biophysica Acta Aug 2007Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as... (Review)
Review
Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates currently used to treat dyslipidemia. PPARalpha regulates the expression of genes encoding proteins that are involved in lipid metabolism, fatty acid oxidation, and glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance. In addition, PPARalpha exerts anti-inflammatory effects both in the vascular wall and the liver. Here we provide an overview of the mechanisms through which PPARalpha affects the initiation and progression of atherosclerosis, with emphasis on the modulation of atherosclerosis-associated inflammatory responses. PPARalpha activation interferes with early steps in atherosclerosis by reducing leukocyte adhesion to activated endothelial cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte migration. In later stages of atherosclerosis, evidence suggests activation of PPARalpha inhibits the formation of macrophage foam cells by regulating expression of genes involved in reverse cholesterol transport, formation of reactive oxygen species (ROS), and associated lipoprotein oxidative modification among others. Furthermore, PPARalpha may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity. These various effects may be linked to the generation of PPARalpha ligands by endogenous mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate PPARalpha in responses such as hypertension and diabetic cardiomyopathy. Although some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular events, other studies have been less clear, in terms of benefit. Independent of the clinical effects of currently used drugs purported to achieve PPARalpha, extensive data establish the importance of PPARalpha in the transcriptional regulation of lipid metabolism, atherosclerosis, and inflammation.
Topics: Atherosclerosis; Cell Adhesion; Cytokines; Endothelium, Vascular; Humans; Inflammation; Leukocytes; Liver; PPAR alpha
PubMed: 17631413
DOI: 10.1016/j.bbalip.2007.04.021 -
Molecular Cancer Apr 2024Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the...
BACKGROUND AND AIMS
Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC.
MATERIALS AND METHODS
A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array.
RESULTS
CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC.
CONCLUSION
Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.
Topics: Humans; Mice; Animals; Sorafenib; Carcinoma, Hepatocellular; RNA, Long Noncoding; Liver Neoplasms; RNA, Guide, CRISPR-Cas Systems; PPAR alpha; Proteomics; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic
PubMed: 38582885
DOI: 10.1186/s12943-024-01988-y