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1.
Biomed Pharmacother ; 179: 117303, 2024 Oct.
Article in English | MEDLINE | ID: mdl-39153437

ABSTRACT

The role of peroxisome proliferator-activated receptor (PPAR)ß/δ in hepatic fibrosis remains a subject of debate. Here, we examined the effects of a PPARß/δ agonist on the pathogenesis of liver fibrosis and the activation of hepatic stellate cells (HSCs), the main effector cells in liver fibrosis, in response to the pro-fibrotic stimulus transforming growth factor-ß (TGF-ß). The PPARß/δ agonist GW501516 completely prevented glucose intolerance and peripheral insulin resistance, blocked the accumulation of collagen in the liver, and attenuated the expression of inflammatory and fibrogenic genes in mice fed a choline-deficient high-fat diet (CD-HFD). The antifibrogenic effect of GW501516 observed in the livers CD-HFD-fed mice could occur through an action on HSCs since primary HSCs isolated from Ppard-/- mice showed increased mRNA levels of the profibrotic gene Col1a1. Moreover, PPARß/δ activation abrogated TGF-ß1-mediated cell migration (an indicator of cell activation) in LX-2 cells (immortalized activated human HSCs). Likewise, GW501516 attenuated the phosphorylation of the main downstream intracellular protein target of TGF-ß1, suppressor of mothers against decapentaplegic (SMAD)3, as well as the levels of the SMAD3 co-activator p300 via the activation of AMP-activated protein kinase (AMPK) and the subsequent inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) in LX-2 cells. Overall, these findings uncover a new mechanism by which the activation of AMPK by a PPARß/δ agonist reduces TGF-ß1-mediated activation of HSCs and fibrosis via the reduction of both SMAD3 phosphorylation and p300 levels.


Subject(s)
AMP-Activated Protein Kinases , E1A-Associated p300 Protein , Hepatic Stellate Cells , Liver Cirrhosis , Mice, Inbred C57BL , PPAR delta , PPAR-beta , Smad3 Protein , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/pathology , Animals , Phosphorylation/drug effects , PPAR-beta/agonists , PPAR-beta/metabolism , PPAR-beta/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , PPAR delta/metabolism , PPAR delta/agonists , PPAR delta/genetics , Smad3 Protein/metabolism , AMP-Activated Protein Kinases/metabolism , E1A-Associated p300 Protein/metabolism , Male , Mice , Humans , Thiazoles/pharmacology , Diet, High-Fat/adverse effects , Mice, Knockout , Insulin Resistance , Cell Line , Transforming Growth Factor beta1/metabolism
2.
Cell Commun Signal ; 22(1): 297, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38807218

ABSTRACT

BACKGROUND: Endoplasmic reticulum (ER) stress-mediated increases in the hepatic levels of the very low-density lipoprotein (VLDL) receptor (VLDLR) promote hepatic steatosis by increasing the delivery of triglyceride-rich lipoproteins to the liver. Here, we examined whether the NAD(+)-dependent deacetylase sirtuin 1 (SIRT1) regulates hepatic lipid accumulation by modulating VLDLR levels and the subsequent uptake of triglyceride-rich lipoproteins. METHODS: Rats fed with fructose in drinking water, Sirt1-/- mice, mice treated with the ER stressor tunicamycin with or without a SIRT1 activator, and human Huh-7 hepatoma cells transfected with siRNA or exposed to tunicamycin or different inhibitors were used. RESULTS: Hepatic SIRT1 protein levels were reduced, while those of VLDLR were upregulated in the rat model of metabolic dysfunction-associated steatotic liver disease (MASLD) induced by fructose-drinking water. Moreover, Sirt1-/- mice displayed increased hepatic VLDLR levels that were not associated with ER stress, but were accompanied by an increased expression of hypoxia-inducible factor 1α (HIF-1α)-target genes. The pharmacological inhibition or gene knockdown of SIRT1 upregulated VLDLR protein levels in the human Huh-7 hepatoma cell line, with this increase abolished by the pharmacological inhibition of HIF-1α. Finally, SIRT1 activation prevented the increase in hepatic VLDLR protein levels in mice treated with the ER stressor tunicamycin. CONCLUSIONS: Overall, these findings suggest that SIRT1 attenuates fatty liver development by modulating hepatic VLDLR levels.


Subject(s)
Liver , Receptors, LDL , Sirtuin 1 , Animals , Sirtuin 1/metabolism , Sirtuin 1/genetics , Humans , Liver/metabolism , Liver/drug effects , Receptors, LDL/metabolism , Receptors, LDL/genetics , Mice , Male , Endoplasmic Reticulum Stress/drug effects , Rats , Cell Line, Tumor , Mice, Knockout , Fatty Liver/metabolism , Fatty Liver/genetics , Fatty Liver/pathology , Mice, Inbred C57BL , Tunicamycin/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Rats, Sprague-Dawley
3.
Article in English | MEDLINE | ID: mdl-38816269

ABSTRACT

Abnormally increased hepatic gluconeogenesis is a significant contributor to hyperglycemia in the fasting state in patients with type 2 diabetes mellitus (T2DM) due to insulin resistance. Metformin, the most prescribed drug for the treatment of T2DM, is believed to exert its effect mainly by reducing hepatic gluconeogenesis. Here, we discuss how increased hepatic gluconeogenesis contributes to T2DM and we review newly revealed mechanisms underlying the attenuation of gluconeogenesis by metformin. In addition, we analyze the recent findings on new determinants involved in the regulation of gluconeogenesis, which might ultimately lead to the identification of novel and targeted treatment strategies for T2DM.

4.
Int J Mol Sci ; 25(5)2024 Feb 23.
Article in English | MEDLINE | ID: mdl-38473843

ABSTRACT

Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy, cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, we analyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders such as Alzheimer's Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a-/-) mice to evaluate AD progression. Behavioral tests showed that Gadd45a-/- mice presented lower working and spatial memory, pointing out an apparent cognitive impairment compared with WT animals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involved in its phosphorylation in the hippocampus. Moreover, Gadd45a-/- animals significantly increased the brain's pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins and the dendritic spine length of the neurons were reduced in Gadd45a-/- mice, which could contribute to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the lack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting that promoting this protein's expression or function might be a promising therapeutic strategy to slow down AD progression.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Mice , Animals , Alzheimer Disease/metabolism , Mice, Transgenic , tau Proteins/metabolism , Cognitive Dysfunction/metabolism , Hippocampus/metabolism , Cognition , Disease Models, Animal
5.
Med Res Rev ; 44(4): 1375-1403, 2024 07.
Article in English | MEDLINE | ID: mdl-38264852

ABSTRACT

The growth arrest and DNA damage inducible (GADD)45 family includes three small and ubiquitously distributed proteins (GADD45A, GADD45B, and GADD45G) that regulate numerous cellular processes associated with stress signaling and injury response. Here, we provide a comprehensive review of the current literature investigating GADD45A, the first discovered member of the family. We first depict how its levels are regulated by a myriad of genotoxic and non-genotoxic stressors, and through the combined action of intricate transcriptional, posttranscriptional, and even, posttranslational mechanisms. GADD45A is a recognized tumor suppressor and, for this reason, we next summarize its role in cancer, as well as the different mechanisms by which it regulates cell cycle, DNA repair, and apoptosis. Beyond these most well-known actions, GADD45A may also influence catabolic and anabolic pathways in the liver, adipose tissue and skeletal muscle, among others. Not surprisingly, GADD45A may trigger AMP-activated protein kinase activity, a master regulator of metabolism, and is known to act as a transcriptional coregulator of numerous nuclear receptors. GADD45A has also been reported to display a cytoprotective role by regulating inflammation, fibrosis and oxidative stress in several organs and tissues, and is regarded an important contributor for the development of heart failure. Overall data point to that GADD45A may play an important role in metabolic, neurodegenerative and cardiovascular diseases, and also autoimmune-related disorders. Thus, the potential mechanisms by which dysregulation of GADD45A activity may contribute to the progression of these diseases are also reviewed below.


Subject(s)
Cell Cycle Proteins , Humans , Animals , Cell Cycle Proteins/metabolism , Neoplasms/metabolism , Nuclear Proteins/metabolism , Apoptosis , GADD45 Proteins
6.
Metabolism ; 152: 155772, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38176644

ABSTRACT

INTRODUCTION: The levels of the cellular energy sensor AMP-activated protein kinase (AMPK) have been reported to be decreased via unknown mechanisms in the liver of mice deficient in growth differentiation factor 15 (GDF15). This stress response cytokine regulates energy metabolism mainly by reducing food intake through its hindbrain receptor GFRAL. OBJECTIVE: To examine how GDF15 regulates AMPK. METHODS: Wild-type and Gdf15-/- mice, mouse primary hepatocytes and the human hepatic cell line Huh-7 were used. RESULTS: Gdf15-/- mice showed glucose intolerance, reduced hepatic phosphorylated AMPK levels, increased levels of phosphorylated mothers against decapentaplegic homolog 3 (SMAD3; a mediator of the fibrotic response), elevated serum levels of transforming growth factor (TGF)-ß1, as well as upregulated gluconeogenesis and fibrosis. In line with these observations, recombinant (r)GDF15 promoted AMPK activation and reduced the levels of phosphorylated SMAD3 and the markers of gluconeogenesis and fibrosis in the liver of mice and in mouse primary hepatocytes, suggesting that these effects may be independent of GFRAL. Pharmacological inhibition of SMAD3 phosphorylation in Gdf15-/- mice prevented glucose intolerance, the deactivation of AMPK and the increase in the levels of proteins involved in gluconeogenesis and fibrosis, suggesting that overactivation of the TGF-ß1/SMAD3 pathway is responsible for the metabolic alterations in Gdf15-/- mice. CONCLUSIONS: Overall, these findings indicate that GDF15 activates AMPK and inhibits gluconeogenesis and fibrosis by lowering the activity of the TGF-ß1/SMAD3 pathway.


Subject(s)
Glucose Intolerance , Transforming Growth Factor beta1 , Humans , AMP-Activated Protein Kinases/metabolism , Fibrosis , Gluconeogenesis , Glucose Intolerance/metabolism , Growth Differentiation Factor 15/genetics , Liver/metabolism , Signal Transduction , Smad3 Protein , Transforming Growth Factor beta1/metabolism
7.
Cell Commun Signal ; 21(1): 326, 2023 11 13.
Article in English | MEDLINE | ID: mdl-37957724

ABSTRACT

BACKGROUND: The placentas from newborns that are small for gestational age (SGA; birth weight < -2 SD for gestational age) may display multiple pathological characteristics. A key determinant of fetal growth and, therefore, birth weight is placental amino acid transport, which is under the control of the serine/threonine kinase mechanistic target of rapamycin (mTOR). The effects of endoplasmic reticulum (ER) stress on the mTOR pathway and the levels of amino acid transporters are not well established. METHODS: Placentas from SGA and appropriate for gestational age (AGA) newborns and the human placental BeWo cell line exposed to the ER stressor tunicamycin were used. RESULTS: We detected a significant increase in the levels of C/EBP homologous protein (CHOP) in the placentas from SGA newborns compared with those from AGA newborns, while the levels of other ER stress markers were barely affected. In addition, placental mTOR Complex 1 (mTORC1) activity and the levels of the mature form of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) were also reduced in the SGA group. Interestingly, CHOP has been reported to upregulate growth arrest and DNA damage-inducible protein 34 (GADD34), which in turn suppresses mTORC1 activity. The GADD34 inhibitor guanabenz attenuated the increase in CHOP protein levels and the reduction in mTORC1 activity caused by the ER stressor tunicamycin in the human placental cell line BeWo, but it did not recover mature SNAT2 protein levels, which might be reduced as a result of defective glycosylation. CONCLUSIONS: Collectively, these data reveal that GADD34A activity and glycosylation are key factors controlling mTORC1 signaling and mature SNAT2 levels in trophoblasts, respectively, and might contribute to the SGA condition. Video Abstract.


Subject(s)
Amino Acid Transport System A , Placenta , TOR Serine-Threonine Kinases , Transcription Factor CHOP , Female , Humans , Infant, Newborn , Pregnancy , Birth Weight , Fetal Growth Retardation/genetics , Fetal Growth Retardation/metabolism , Gestational Age , Mechanistic Target of Rapamycin Complex 1/metabolism , Placenta/metabolism , TOR Serine-Threonine Kinases/metabolism , Tunicamycin/pharmacology , Up-Regulation , Transcription Factor CHOP/genetics , Amino Acid Transport System A/genetics
8.
Biomed Pharmacother ; 167: 115623, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37783154

ABSTRACT

Elafibranor is a dual peroxisome proliferator-activated receptor (PPAR)α and ß/δ agonist that has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we examined the effects of elafibranor in mice fed a choline-deficient high-fat diet (CD-HFD), a model of metabolic dysfunction-associated steatohepatitis (MASH) that presents obesity and insulin resistance. Our findings revealed that elafibranor treatment ameliorated steatosis, inflammation, and fibrogenesis in the livers of CD-HFD-fed mice. Unexpectedly, elafibranor also increased the levels of the epithelial-mesenchymal transition (EMT)-promoting protein S100A4 via PPARß/δ activation. The increase in S100A4 protein levels caused by elafibranor was accompanied by changes in the levels of markers associated with the EMT program. The S100A4 induction caused by elafibranor was confirmed in the BRL-3A rat liver cells and a mouse primary hepatocyte culture. Furthermore, elafibranor reduced the levels of ASB2, a protein that promotes S100A4 degradation, while ASB2 overexpression prevented the stimulating effect of elafibranor on S100A4. Collectively, these findings reveal an unexpected hepatic effect of elafibranor on increasing S100A4 and promoting the EMT program.


Subject(s)
Non-alcoholic Fatty Liver Disease , PPAR delta , PPAR-beta , Animals , Mice , Rats , Diet, High-Fat , Epithelial-Mesenchymal Transition , Liver , Non-alcoholic Fatty Liver Disease/metabolism , PPAR delta/metabolism , PPAR-beta/agonists , PPAR-beta/metabolism , PPAR-beta/therapeutic use
9.
Biomed Pharmacother ; 168: 115667, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37826940

ABSTRACT

Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the key role of these kinases on endoplasmic reticulum (ER) stress, ALT-PG2 attenuated the levels of ER stress and inflammatory markers. Overall, the findings of this study indicate that targeting sEH with degraders is a promising pharmacological strategy to promote AMPK activation and to reduce ER stress and inflammation.


Subject(s)
Epoxide Hydrolases , Neurodegenerative Diseases , Humans , Animals , Mice , AMP-Activated Protein Kinases/metabolism , Inflammation , Endoplasmic Reticulum Stress/physiology
10.
Molecules ; 28(14)2023 Jul 17.
Article in English | MEDLINE | ID: mdl-37513338

ABSTRACT

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618.


Subject(s)
Diabetes Mellitus, Type 2 , Metformin , Humans , AMP-Activated Protein Kinases , Growth Differentiation Factor 15/genetics , Growth Differentiation Factor 15/metabolism , Metformin/pharmacology , RNA, Messenger
11.
Trends Pharmacol Sci ; 44(7): 457-473, 2023 07.
Article in English | MEDLINE | ID: mdl-37188578

ABSTRACT

Metformin is the most prescribed drug for the treatment of type 2 diabetes mellitus (T2DM), but its mechanism of action has not yet been completely elucidated. Classically, the liver has been considered the major site of action of metformin. However, over the past few years, advances have unveiled the gut as an additional important target of metformin, which contributes to its glucose-lowering effect through new mechanisms of action. A better understanding of the mechanistic details of metformin action in the gut and the liver and its relevance in patients remains the challenge of present and future research and may impact drug development for the treatment of T2DM. Here, we offer a critical analysis of the current status of metformin-driven multiorgan glucose-lowering effects.


Subject(s)
Diabetes Mellitus, Type 2 , Metformin , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Metformin/pharmacology , Metformin/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Liver , Glucose
12.
Pharmacol Res ; 187: 106578, 2023 01.
Article in English | MEDLINE | ID: mdl-36435271

ABSTRACT

BACKGROUND AND AIMS: Metformin, the most prescribed drug for the treatment of type 2 diabetes mellitus, has been recently reported to promote weight loss by upregulating the anorectic cytokine growth differentiation factor 15 (GDF15). Since the antidiabetic effects of metformin are mostly mediated by the activation of AMPK, a key metabolic sensor in energy homeostasis, we examined whether the activation of this kinase by metformin was dependent on GDF15. METHODS: Cultured hepatocytes and myotubes, and wild-type and Gdf15-/- mice were utilized in a series of studies to investigate the involvement of GDF15 in the activation of AMPK by metformin. RESULTS: A low dose of metformin increased GDF15 levels without significantly reducing body weight or food intake, but it ameliorated glucose intolerance and activated AMPK in the liver and skeletal muscle of wild-type mice but not Gdf15-/- mice fed a high-fat diet. Cultured hepatocytes and myotubes treated with metformin showed AMPK-mediated increases in GDF15 levels independently of its central receptor GFRAL, while Gdf15 knockdown blunted the effect of metformin on AMPK activation, suggesting that AMPK is required for the metformin-mediated increase in GDF15, which in turn is needed to sustain the full activation of this kinase independently of the CNS. CONCLUSION: Overall, these findings uncover a novel mechanism through which GDF15 upregulation by metformin is involved in achieving and sustaining full AMPK activation by this drug independently of the CNS.


Subject(s)
AMP-Activated Protein Kinases , Diabetes Mellitus, Type 2 , Growth Differentiation Factor 15 , Hypoglycemic Agents , Metformin , Animals , Mice , AMP-Activated Protein Kinases/metabolism , Diabetes Mellitus, Type 2/drug therapy , Growth Differentiation Factor 15/genetics , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Metformin/pharmacology , Metformin/therapeutic use , Feedback, Physiological
13.
Trends Endocrinol Metab ; 33(11): 741-754, 2022 11.
Article in English | MEDLINE | ID: mdl-36151002

ABSTRACT

Although a large number of drugs are available for the treatment of type 2 diabetes mellitus (T2DM), many patients do not achieve adequate disease control despite adhering to medication. Recent findings indicate that the pharmacological modulation of the stress-induced cytokine growth differentiation factor 15 (GDF15) shows promise for the treatment of T2DM. GDF15 suppresses appetite and reduces inflammation, increases thermogenesis and lipid catabolism, sustains AMP-activated protein kinase (AMPK) activity, and ameliorates insulin resistance and hepatic steatosis. In addition, circulating GDF15 levels are elevated in response to several antidiabetic drugs, including metformin, with GDF15 mediating some of their effects. Here, we review the mechanistic insights into the beneficial effects of recently explored therapeutic approaches that target GDF15 for the treatment of T2DM.


Subject(s)
Diabetes Mellitus, Type 2 , Metformin , Humans , Growth Differentiation Factor 15/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , AMP-Activated Protein Kinases/metabolism , Hypoglycemic Agents/therapeutic use , Metformin/pharmacology , Metformin/therapeutic use , Lipids
14.
Cell Commun Signal ; 20(1): 53, 2022 04 15.
Article in English | MEDLINE | ID: mdl-35428325

ABSTRACT

BACKGROUND: Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) downregulation in skeletal muscle contributes to insulin resistance and type 2 diabetes mellitus. Here, we examined the effects of endoplasmic reticulum (ER) stress on PGC-1α levels in muscle and the potential mechanisms involved. METHODS: The human skeletal muscle cell line LHCN-M2 and mice exposed to different inducers of ER stress were used. RESULTS: Palmitate- or tunicamycin-induced ER stress resulted in PGC-1α downregulation and enhanced expression of activating transcription factor 4 (ATF4) in human myotubes and mouse skeletal muscle. Overexpression of ATF4 decreased basal PCG-1α expression, whereas ATF4 knockdown abrogated the reduction of PCG-1α caused by tunicamycin in myotubes. ER stress induction also activated mammalian target of rapamycin (mTOR) in myotubes and reduced the nuclear levels of cAMP response element-binding protein (CREB)-regulated transcription co-activator 2 (CRTC2), a positive modulator of PGC-1α transcription. The mTOR inhibitor torin 1 restored PCG-1α and CRTC2 protein levels. Moreover, siRNA against S6 kinase, an mTORC1 downstream target, prevented the reduction in the expression of CRTC2 and PGC-1α caused by the ER stressor tunicamycin. CONCLUSIONS: Collectively, these findings demonstrate that ATF4 and the mTOR-CRTC2 axis regulates PGC-1α transcription under ER stress conditions in skeletal muscle, suggesting that its inhibition might be a therapeutic target for insulin resistant states. Video Abstract.


Subject(s)
Activating Transcription Factor 4 , Diabetes Mellitus, Type 2 , Endoplasmic Reticulum Stress , Muscle, Skeletal , TOR Serine-Threonine Kinases , Transcription Factors , Activating Transcription Factor 4/metabolism , Animals , Diabetes Mellitus, Type 2/metabolism , Down-Regulation , Mice , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/metabolism , TOR Serine-Threonine Kinases/metabolism , Transcription Factors/metabolism , Tunicamycin/metabolism , Tunicamycin/pharmacology
15.
Int J Mol Sci ; 22(16)2021 Aug 09.
Article in English | MEDLINE | ID: mdl-34445261

ABSTRACT

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)ß/δ show promise. Remarkably, most of the antidiabetic effects of PPARß/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARß/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARß/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/prevention & control , Insulin Resistance , PPAR delta/metabolism , PPAR-beta/metabolism , AMP-Activated Protein Kinases/genetics , Animals , Diabetes Mellitus, Type 2/genetics , Humans , PPAR delta/genetics , PPAR-beta/genetics , Signal Transduction/drug effects , Signal Transduction/genetics
16.
Cell Rep ; 36(6): 109501, 2021 08 10.
Article in English | MEDLINE | ID: mdl-34380027

ABSTRACT

Peroxisome proliferator-activated receptor ß/δ (PPARß/δ) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examine whether PPARß/δ activation effects depend on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPARß/δ activation increases GDF15 levels and ameliorates glucose intolerance, fatty acid oxidation, endoplasmic reticulum stress, and inflammation, and activates AMPK in HFD-fed mice, whereas these effects are abrogated by the injection of a GDF15 neutralizing antibody and in Gdf15-/- mice. The AMPK-p53 pathway is involved in the PPARß/δ-mediated increase in GDF15, which in turn activates again AMPK. Consistently, Gdf15-/- mice show reduced AMPK activation in skeletal muscle, whereas GDF15 administration results in AMPK activation in this organ. Collectively, these data reveal a mechanism by which PPARß/δ activation increases GDF15 levels via AMPK and p53, which in turn mediates the metabolic effects of PPARß/δ by sustaining AMPK activation.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Growth Differentiation Factor 15/metabolism , PPAR delta/metabolism , PPAR-beta/metabolism , Adenylate Kinase/metabolism , Animals , Cell Line , Endoplasmic Reticulum Stress , Enzyme Activation , Growth Differentiation Factor 15/deficiency , Inflammation/pathology , Insulin/metabolism , Lipid Metabolism , Liver/metabolism , Liver/pathology , Mice, Inbred C57BL , Mice, Knockout , Muscle, Skeletal/metabolism , Signal Transduction , Tumor Suppressor Protein p53/metabolism
17.
Trends Mol Med ; 27(6): 554-571, 2021 06.
Article in English | MEDLINE | ID: mdl-33839024

ABSTRACT

Diabetic cardiomyopathy is the leading cause of death among people with diabetes. Despite its severity and poor prognosis, there are currently no approved specific drugs to prevent or even treat diabetic cardiomyopathy. There is a need to understand the pathogenic mechanisms underlying the development of diabetic cardiomyopathy to design new therapeutic strategies. These mechanisms are complex and intricate and include metabolic dysregulation, inflammation, oxidative stress, fibrosis, and apoptosis. Sirtuins, a group of deacetylase enzymes, play an important role in all these processes and are, therefore, potential molecular targets for treating this disease. In this review, we discuss the role of sirtuins in the heart, focusing on their contribution to the pathogenesis of diabetic cardiomyopathy and how their modulation could be therapeutically useful.


Subject(s)
Diabetes Mellitus/physiopathology , Diabetic Cardiomyopathies/pathology , Inflammation/physiopathology , Oxidative Stress , Signal Transduction , Sirtuins/metabolism , Animals , Diabetic Cardiomyopathies/metabolism , Humans
18.
Clín. investig. arterioscler. (Ed. impr.) ; 33(2): 108-115, Mar-Abr. 2021. ilus
Article in English | IBECS | ID: ibc-220863

ABSTRACT

Apolipoprotein C-III (apoC-III) is a small protein that is predominantly synthesized in the liver and mainly resides at the surface of triglyceride-rich lipoproteins. Its expression is upregulated by glucose and reduced by insulin, with enhanced apoC-III promoting hypertriglyceridemia and inflammation in vascular cells. The protein is also elevated in patients with diabetes, suggesting that enhanced apoC-III levels might contribute to the development of type 2 diabetes mellitus. The present review focuses on the key mechanisms by which apoC-III could promote type 2 diabetes mellitus, including exacerbation of insulin resistance in skeletal muscle, activation of β-cell apoptosis, promotion of weight gain through its effects on white adipose tissue and hypothalamus, and attenuation of the beneficial effects of high-density lipoproteins on glucose metabolism. Therapeutic strategies aimed at reducing apoC-III levels may not only reduce hypertriglyceridemia but also might improve insulin resistance, thus delaying the development of type 2 diabetes mellitus.(AU)


La apolipoproteína C-III (apoC-III) es una pequeña proteína predominantemente sintetizada en el hígado y que se encuentra principalmente en la superficie de las lipoproteínas ricas en triglicéridos. Su expresión es aumentada por la glucosa y reducida por la insulina, y sus niveles elevados promueven la hipertrigliceridemia, así como la inflamación en células vasculares. Esta proteína también se encuentra elevada en los pacientes diabéticos, lo que sugiere que el aumento de esta apoproteína podría contribuir al desarrollo de la diabetes mellitus de tipo 2. Esta revisión aborda los mecanismos clave por los que la apoC-III podría promover la diabetes mellitus tipo 2, entre los que se encuentran la exacerbación de la resistencia a la insulina en el músculo esquelético, la activación de la apoptosis en la célula β, la promoción del aumento de peso por sus efectos sobre el tejido adiposo blanco y el hipotálamo, y la atenuación de los efectos beneficiosos de las lipoproteínas de alta densidad sobre el metabolismo de la glucosa. Las estrategias terapéuticas dirigidas a disminuir los niveles de apoC-III no sólo podrían reducir la hipertrigliceridemia, sino también mejorar la resistencia a la insulina y retrasar el desarrollo de la diabetes mellitus de tipo 2.(AU)


Subject(s)
Humans , Apolipoprotein C-III , Insulin Resistance , Hyperlipidemias , Diabetes Mellitus, Type 2
19.
Metabolism ; 114: 154342, 2021 01.
Article in English | MEDLINE | ID: mdl-32810487

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD), a form of chronic liver disease that occurs in individuals with no significant alcohol abuse, has become an increasing concern for global health. NAFLD is defined as the presence of lipid deposits in hepatocytes and it ranges from hepatic steatosis (fatty liver) to steatohepatitis. Emerging data from both preclinical studies and clinical trials suggest that the peroxisome proliferator-activated receptor (PPAR)ß/δ plays an important role in the control of carbohydrate and lipid metabolism in liver, and its activation might hinder the progression of NAFLD. Here, we review the latest information on the effects of PPARß/δ on NAFLD, including its capacity to reduce lipogenesis, to alleviate inflammation and endoplasmic reticulum stress, to ameliorate insulin resistance, and to attenuate liver injury. Because of these effects, activation of hepatic PPARß/δ through synthetic or natural ligands provides a promising therapeutic option for the management of NAFLD.


Subject(s)
Liver/metabolism , Non-alcoholic Fatty Liver Disease/metabolism , PPAR delta/metabolism , PPAR-beta/metabolism , Animals , Hepatocytes/metabolism , Humans , Lipid Metabolism/physiology
20.
Clin Investig Arterioscler ; 33(2): 108-115, 2021.
Article in English, Spanish | MEDLINE | ID: mdl-33303217

ABSTRACT

Apolipoprotein C-III (apoC-III) is a small protein that is predominantly synthesized in the liver and mainly resides at the surface of triglyceride-rich lipoproteins. Its expression is upregulated by glucose and reduced by insulin, with enhanced apoC-III promoting hypertriglyceridemia and inflammation in vascular cells. The protein is also elevated in patients with diabetes, suggesting that enhanced apoC-III levels might contribute to the development of type 2 diabetes mellitus. The present review focuses on the key mechanisms by which apoC-III could promote type 2 diabetes mellitus, including exacerbation of insulin resistance in skeletal muscle, activation of ß-cell apoptosis, promotion of weight gain through its effects on white adipose tissue and hypothalamus, and attenuation of the beneficial effects of high-density lipoproteins on glucose metabolism. Therapeutic strategies aimed at reducing apoC-III levels may not only reduce hypertriglyceridemia but also might improve insulin resistance, thus delaying the development of type 2 diabetes mellitus.


Subject(s)
Apolipoprotein C-III/metabolism , Diabetes Mellitus, Type 2/physiopathology , Insulin Resistance/physiology , Animals , Apolipoprotein C-III/genetics , Diabetes Mellitus, Type 2/prevention & control , Gene Expression Regulation , Glucose/metabolism , Humans , Hypertriglyceridemia/physiopathology , Hypertriglyceridemia/prevention & control , Insulin/metabolism , Lipoproteins, HDL/metabolism
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