Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk

Sinha, Rohit Anthony; Rajak, Sangam; Singh, Brijesh Kumar; Yen, Paul M.

doi:10.3390/ijms21072391

Cited by 36 publications

(27 citation statements)

References 97 publications

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“…During fasting, PPARα also increases the transcription of genes involved in autophagy, leading to lipophagy, a mechanism involved in hepatic lipid catabolism [248]. Interestingly, there is reciprocal regulation of PPARα and the autophagy-lysosomal signal [249]. Lysosomal inhibition leads to downregulation of PPARα and its target genes, decreasing peroxisomal lipid oxidation and biogenesis [250].…”

Section: Ppars In Glucose and Lipid Metabolismmentioning

confidence: 99%

“…In addition, PPARγ has anti-fibrotic effects, but the roles of PPARα and PPARβ/δ in HSCs are not fully elucidated and require further study. [235,237,321,322], autophagy (Atg, Tfeb) [248,249], and glycerol metabolism (Gyk, Gpdh) [255], and regulates lipoprotein metabolism (Lpl, ApoC3) [220] and hepatic Fgf21 expression [242,243]. It also downregulates inflammatory genes and transcription factors (Nf-κb, Ap-1, Stat, Iκb, Il1ra) [220,281,300], and may downregulate Tgfβ expression [306].…”

Section: Ppars In Inflammation and Hsc Activationmentioning

confidence: 99%

“…PPARγ downregulates inflammatory transcription factors (Nf-κb, Ap-1, Stat) [312,315] and may also reduce expression of Tgfβ [318,319]. Abbreviations: Hmgcs2, 3hydroxy-3-methylglutaryl-CoA synthase 2; Acox, peroxisomal acyl-coenzyme A oxidase 1; Cyp4a, cytochrome P450 family 4 subfamily A; Ehhadh, enoyl-CoA hydratase and 3-hydroxyacyl CoA dehydrogenase; Acadm, acyl-CoA dehydrogenase medium chain; Acadl, acyl-CoA dehydrogenase long chain; Acadvl, acyl-CoA dehydrogenase very long chain; Cpt1a, carnitine palmitoyltransferase 1a; Cpt2, carnitine palmitoyltransferase 2; Slc27a1, solute carrier family 27 member 1; Fabp1, fatty acid binding protein 1; Fabp4, fatty acid binding protein 4; Lpl, lipoprotein lipase; ApoC3, apolipoprotein C3; ApoA4, apolipoprotein A4; Atg, autophagy-related genes; Tfeb, transcription factor EB; Fgf21, [235,237,321,322], autophagy (Atg, Tfeb) [248,249], and glycerol metabolism (Gyk, Gpdh) [255], and regulates lipoprotein metabolism (Lpl, ApoC3) [220] and hepatic Fgf21 expression [242,243]. It also downregulates inflammatory genes and transcription factors (Nf-κb, Ap-1, Stat, Iκb, Il1ra) [220,281,300], and may downregulate Tgfβ expression [306].…”

Section: Ppars In Inflammation and Hsc Activationmentioning

confidence: 99%

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Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Fougerat

Montagner

Loiseau

et al. 2020

Cells

103

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Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.

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Section: Ppars In Glucose and Lipid Metabolismmentioning

confidence: 99%

Section: Ppars In Inflammation and Hsc Activationmentioning

confidence: 99%

Section: Ppars In Inflammation and Hsc Activationmentioning

confidence: 99%

See 1 more Smart Citation

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Fougerat

Montagner

Loiseau

et al. 2020

Cells

103

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“…Our results uncover a novel autophagy independent signaling by ULK1, which involves the regulation of anabolic AKT signaling and nuclear activity of FOXO transcription factor. Although the autophagy-lysosomal pathway is known to regulate nuclear receptor action (Siong Tan et al, 2019;Sinha et al, 2020), the direct effect of ULK1 on nuclear receptor/transcription factor activity remains less explored. As FOXO3a and related FOXO family proteins are involved in a myriad of cellular processes and human diseases (Lee and Dong, 2017), the modulation of ULK1 opens an exciting possibility of targeting FOXO related disorders.…”

Section: Discussionmentioning

confidence: 99%

Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells

Rajak

Iannucci

Zhou

et al. 2020

Front. Cell Dev. Biol.

Self Cite

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The hepatic mevalonate (MVA) pathway, responsible for cholesterol biosynthesis, is a therapeutically important metabolic pathway in clinical medicine. Using an unbiased transcriptomics approach, we uncover a novel role of Unc-51 like autophagy activating kinase 1 (ULK1) in regulating the expression of the hepatic de novo cholesterol biosynthesis/MVA pathway genes. Genetic silencing of ULK1 in non-starved mouse (AML-12) and human (HepG2) hepatic cells as well as in mouse liver followed by transcriptome and pathway analysis revealed that the loss of ULK1 expression led to significant down-regulation of genes involved in the MVA/cholesterol biosynthesis pathway. At a mechanistic level, loss of ULK1 led to decreased expression of SREBF2/SREBP2 (sterol regulatory element binding factor 2) via its effects on AKT-FOXO3a signaling and repression of SREBF2 target genes in the MVA pathway. Our findings, therefore, discover ULK1 as a novel regulator of cholesterol biosynthesis and a possible druggable target for controlling cholesterol-associated pathologies.

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“…PPARs play a key role in lipid metabolism [272,273]. PPARα improves catabolism and lipid mobilization [274], while PPARγ promotes lipid synthesis and LD formation [275][276][277] and PPARδ increases the synthesis of high-density lipoprotein (HDL), inhibits LD formation in the liver, improves FFA catabolism, and promotes energy uncoupling in adipose and muscular tissues [278,279].…”

Section: The 35-t2 and Lipid Metabolismmentioning

confidence: 99%

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

Giammanco

Schiera

Liegro

2020

IJMS

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Since the realization that the cellular homologs of a gene found in the retrovirus that contributes to erythroblastosis in birds (v-erbA), i.e. the proto-oncogene c-erbA encodes the nuclear receptors for thyroid hormones (THs), most of the interest for THs focalized on their ability to control gene transcription. It was found, indeed, that, by regulating gene expression in many tissues, these hormones could mediate critical events both in development and in adult organisms. Among their effects, much attention was given to their ability to increase energy expenditure, and they were early proposed as anti-obesity drugs. However, their clinical use has been strongly challenged by the concomitant onset of toxic effects, especially on the heart. Notably, it has been clearly demonstrated that, besides their direct action on transcription (genomic effects), THs also have non-genomic effects, mediated by cell membrane and/or mitochondrial binding sites, and sometimes triggered by their endogenous catabolites. Among these latter molecules, 3,5-diiodo-L-thyronine (3,5-T2) has been attracting increasing interest because some of its metabolic effects are similar to those induced by T3, but it seems to be safer. The main target of 3,5-T2 appears to be the mitochondria, and it has been hypothesized that, by acting mainly on mitochondrial function and oxidative stress, 3,5-T2 might prevent and revert tissue damages and hepatic steatosis induced by a hyper-lipid diet, while concomitantly reducing the circulating levels of low density lipoproteins (LDL) and triglycerides. Besides a summary concerning general metabolism of THs, as well as their genomic and non-genomic effects, herein we will discuss resistance to THs and the possible mechanisms of action of 3,5-T2, also in relation to its possible clinical use as a drug.

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Hepatic Lipid Catabolism via PPARα-Lysosomal Crosstalk

Cited by 36 publications

References 97 publications

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

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