Garland Science. Current Opinion in Cell Biology. Annual Review of Biochemistry. The Journal of Pathology.

S2CID Metabolism , catabolism , anabolism. Metabolic pathway Metabolic network Primary nutritional groups. Purine metabolism Nucleotide salvage Pyrimidine metabolism Purine nucleotide cycle. Pentose phosphate pathway Fructolysis Polyol pathway Galactolysis Leloir pathway.

Glycosylation N-linked O-linked. Photosynthesis Anoxygenic photosynthesis Chemosynthesis Carbon fixation DeLey-Doudoroff pathway Entner-Doudoroff pathway. Xylose metabolism Radiotrophism. Fatty acid degradation Beta oxidation Fatty acid synthesis. Steroid metabolism Sphingolipid metabolism Eicosanoid metabolism Ketosis Reverse cholesterol transport.

Metal metabolism Iron metabolism Ethanol metabolism Phospagen system ATP-PCr. Metabolism map. Carbon fixation. Photo- respiration. Pentose phosphate pathway. Citric acid cycle. Glyoxylate cycle. Urea cycle. Fatty acid synthesis. Fatty acid elongation.

Beta oxidation. beta oxidation. Glyco- genolysis. Glyco- genesis. Glyco- lysis. Gluconeo- genesis. Pyruvate decarb- oxylation. Keto- lysis. Keto- genesis. feeders to gluconeo- genesis.

Light reaction. Oxidative phosphorylation. Amino acid deamination. Citrate shuttle. MVA pathway. MEP pathway.

Shikimate pathway. Glycosyl- ation. Sugar acids. Simple sugars. Nucleotide sugars. Propionyl -CoA. Acetyl -CoA.

Oxalo- acetate. Succinyl -CoA. α-Keto- glutarate. Ketone bodies. Respiratory chain. Serine group. Branched-chain amino acids. Aspartate group. Amino acids. Ascorbate vitamin C. Bile pigments. Cobalamins vitamin B Various vitamin Bs. Calciferols vitamin D.

Retinoids vitamin A. Nucleic acids. Terpenoid backbones. Bile acids. Glycero- phospholipids. Fatty acids. Glyco- sphingolipids. Polyunsaturated fatty acids. Endo- cannabinoids. ATP citrate lyase Acetyl-CoA carboxylase.

Beta-ketoacyl-ACP synthase Β-Ketoacyl ACP reductase 3-Hydroxyacyl ACP dehydrase Enoyl ACP reductase. Stearoyl-CoA desaturase Glycerolphosphate dehydrogenase Thiokinase. Carnitine palmitoyltransferase I Carnitine-acylcarnitine translocase Carnitine palmitoyltransferase II.

Acyl CoA dehydrogenase ACADL ACADM ACADS ACADVL ACADSB Enoyl-CoA hydratase MTP : HADH HADHA HADHB Acetyl-CoA C-acyltransferase. Enoyl CoA isomerase 2,4 Dienoyl-CoA reductase. Propionyl-CoA carboxylase. Hydroxyacyl-Coenzyme A dehydrogenase. Malonyl-CoA decarboxylase. Long-chain-aldehyde dehydrogenase.

Metabolism : lipid metabolism — eicosanoid metabolism enzymes. Phospholipase A2 Phospholipase C Diacylglycerol lipase.

Cyclooxygenase PTGS1 PTGS2 PGD2 synthase PGE synthase Prostaglandin-E2 9-reductase PGI2 synthase TXA synthase. Metabolism , lipid metabolism , glycolipid enzymes. Glycosyltransferase Sulfotransferase.

From ganglioside Beta-galactosidase Hexosaminidase A Neuraminidase Glucocerebrosidase From globoside Hexosaminidase B Alpha-galactosidase Beta-galactosidase Glucocerebrosidase From sphingomyelin Sphingomyelin phosphodiesterase Sphingomyelin phosphodiesterase 1 From sulfatide Arylsulfatase A Galactosylceramidase.

Ceramidase ACER1 ACER2 ACER3 ASAH1 ASAH2 ASAH2B ASAH2C. Sphingosine kinase. Palmitoyl protein thioesterase Tripeptidyl peptidase I CLN3 CLN5 CLN6 CLN8. Serine C-palmitoyltransferase SPTLC1 Ceramide glucosyltransferase UGCG.

Acetyl-Coenzyme A acetyltransferase HMG-CoA synthase regulated step. HMG-CoA lyase 3-hydroxybutyrate dehydrogenase Thiophorase. HMG-CoA reductase. Mevalonate kinase Phosphomevalonate kinase Pyrophosphomevalonate decarboxylase Isopentenyl-diphosphate delta isomerase. Dimethylallyltranstransferase Geranyl pyrophosphate.

Farnesyl-diphosphate farnesyltransferase Squalene monooxygenase Lanosterol synthase. Lanosterol 14α-demethylase Sterol-C5-desaturase-like 7-Dehydrocholesterol reductase. Cholesterol 7α-hydroxylase Sterol hydroxylase.

Cholesterol side-chain cleavage. Aromatase 17β- HSD. Steroid metabolism : sulfatase Steroid sulfatase sulfotransferase SULT1A1 SULT2A1 Steroidogenic acute regulatory protein Cholesterol total synthesis Reverse cholesterol transport.

Authority control databases : National Germany Israel United States Latvia Czech Republic 2. Categories : Lipids Metabolism. Studies in global- and β-cell-specific ATGL and HSL-deficient mice revealed impaired GSIS of isolated pancreatic islets and hypoinsulinemia 26 , 31 , , , , In contrast, inhibition of LAL in pancreatic β-cells indirectly potentiates GSIS by activating ATGL and HSL Several mechanisms have been proposed for impaired insulin secretion in ATGL-deficient β-cells, including 1 reduced availability of PPARδ ligands resulting in mitochondrial dysfunction 31 , 2 reduced generation of MGs that induce insulin exocytosis by binding to the vesicle priming protein Munc13—1 refs.

Moreover, FAs liberated from adipose tissue promote insulin secretion after β-adrenergic stimulation and reduced or diminished adipocyte ATGL or HSL activity perturbs insulin secretion from β-cells 27 , , , , Hence, specifically manipulating adipocyte lipolysis may represent a potential pharmacological approach to improve insulin sensitivity and glucose tolerance.

Obesity-associated NAFLD results from either increased de novo TG synthesis in the liver or increased flux of FAs from adipose tissue to the liver, or both Accordingly, reduced FA mobilization from adipocytes ameliorates hepatic steatosis, inflammation and fibrosis in high-fat-diet-fed mice that have adipocyte-specific ATGL deficiency or CGI deficiency or that have been treated with atglistatin , , Somewhat counterintuitively, overexpression of ATGL in adipocytes also improves hepatic steatosis in a transgenic mouse model However, evidence shows that enhanced FA oxidation in adipose tissues of adipocyte-specific ATGL transgenic mice reduces FA flux to the liver, resulting in decreased hepatic fat storage.

Numerous GWAS and candidate-gene studies have demonstrated that the PNPLA3-IM variant represents a strong genetic risk factor for steatohepatitis, fibrosis and HCC ASO-mediated silencing of PNPLA3 improved NAFLD and fibrosis in a mutant knock-in mouse model harbouring the PNPLA3-IM mutation Moreover, PNPLA3-IM sequesters CGI from its interaction with ATGL and impairs its hydrolytic activity for LD-associated TGs This therapeutic concept is corroborated by the finding that diet-induced hepatic steatosis is prevented by adenovirus-mediated overexpression of ATGL in murine livers Chronic heart failure HF is a common disease resulting from any structural or functional impairment of ventricular filling or ejection of blood HF represents a leading cause of death and can basically be subdivided into two distinct groups: HF with preserved ejection fraction HFpEF and HF with restricted ejection fraction HFrEF The healthy heart exhibits high flexibility to use FA, glucose and ketone bodies as energy substrates During cardiac failure, metabolic flexibility is reduced, and the heart increasingly uses glucose as energy fuel However, a chronic activation of the sympathetic nervous system and an increase in natriuretic peptides augments adipose FA mobilization, which competes with glucose utilization and aggravates oxidative stress during HF , , Accordingly, adipocyte-specific ATGL deficiency or atglistatin treatment protected mice from pressure-induced cardiac hypertrophy and cardiac fibrosis , Similarly, ATGL inhibition promoted a cardioprotective effect in a mouse model of catecholamine-induced cardiac damage It has been suggested that inhibition of adipocyte ATGL activity improves cardiac energy metabolism by further shifting substrate utilization from FAs towards glucose and by changing the cardiac membrane lipid composition Considering the current lack of effective therapeutics, the pharmacological inhibition of ATGL, and possibly other lipases in adipose tissue, may represent a promising approach to treat HFpEF.

Importantly, however, the inhibition of lipolysis must be restricted to adipose tissue because concomitant suppression of lipolysis in cardiac myocytes, hepatocytes and other non-adipose tissues may result in steatosis and organ dysfunction, as present in people with global ATGL 21 , 23 or CGI deficiency Cachexia is a severe wasting disorder accompanying the late stage of various diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease, burn-induced trauma or cancer The occurrence of cachexia in any of these maladies drastically decreases treatment options and chances of survival.

Cachexia is a hypermetabolic disorder characterized by systemic inflammation and an unintended loss of body weight due to a reduction in adipose tissue and skeletal muscle mass that cannot be reversed by increased nutritional intake , To date, the multifactorial mechanisms causing cachexia are yet insufficiently understood and effective treatments are not available.

Adipose tissue loss often precedes muscle loss in cachexia, and some studies have provided evidence that halting fat depletion also preserves muscle mass , Mechanistically, adipose tissue undergoes a switch towards catabolism that is initiated by proinflammatory cytokines and amplified by β-adrenergic signals , This catabolic reprogramming elevates lipolysis and futile cycling, but reduces lipogenesis and fat accumulation, leading to adipose tissue atrophy , Reducing lipolysis by pharmacological or genetic inhibition of ATGL , or by targeting the erroneously prolipolytic signals, like the β3-adrenergic signal or the AMPK—CIDEA axis , prevented adipose-tissue loss in murine cachexia models of burn-induced trauma or cancer.

Interestingly, ATGL blockade not only reduced lipolysis but also prevented browning of WAT and fatty-liver development post burn injury and muscle atrophy in some mouse models of cancer cachexia The mechanisms underlying the tumour—adipose tissue—muscle crosstalk in cachexia and the question of whether lipolysis inhibition affects cachexia in humans await future clarification.

Discoveries in the past two decades have turned intracellular TG catabolism from a relatively simple, single-enzyme reaction by HSL to a complex, highly regulated pathway that affects energy homeostasis on numerous levels.

While canonical lipolysis of intracellular lipid stores is by now relatively well-characterized, the contribution of noncanonical enzymes and the role of lysosomal acid lipolysis for cytoplasmic LD degradation require comprehensive characterization.

In many cases, the enzymatic function of these proteins as well as their placement in lipid metabolism and physiology remain unclear, despite compelling evidence for their relevance in disease development.

A good example for such dreadful lack of knowledge relates to the crucial yet unsettled function of PNPLA3 in lipid metabolism and liver disease. Another exciting topic of future research will address the therapeutic potential of lipolytic enzymes to treat metabolic disorders.

Examples include inhibition of ATGL and possibly HSL to treat or prevent type 2 diabetes, fatty liver disease, lethal heart failure or cachexia. While preclinical experiments in mice are promising, their potential in humans remains completely unknown. Similarly, it is of utmost interest to find out whether inhibition of PNPLA3 prevents NASH, liver cirrhosis and liver cancer in humans.

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