Transport of glycerol from adipocytes to liver by aquaporins (Homo sapiens)
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Description
Ghrelin is a peptide hormone of 28 amino acid residues which is acylated at the serine-3 of the mature peptide. Ghrelin is synthesized in several tissues: X/A-like cells of the gastric mucosa (the major source of ghrelin), hypothalamus, pituitary, adrenal gland, thyroid, breast, ovary, placenta, fallopian tube, testis, prostate, liver, gall bladder, pancreas, fat tissue, human lymphocytes, spleen, kidney, lung, skeletal muscle, myocardium, vein and skin. Ghrelin binds the GHS-R1a receptor present in hypothalamus pituitary, and other tissues. Binding causes appetite stimulation and release of growth hormone. Levels of circulating ghrelin rise during fasting, peak before a meal, and fall according to the calories ingested.
Preproghrelin is cleaved to yield proghrelin which is then acylated by ghrelin O-acyltransferase to yield octanoyl ghrelin and decanoyl ghrelin. Only octanoyl ghrelin is able to bind and activate the GHS-R1a receptor. Unacylated ghrelin (des-acyl ghrelin) is also present in plasma but its function is controversial.
Acyl proghrelin is cleaved by prohormone convertase 1/3 to yield the mature acyl ghrelin and C-ghrelin. Secretion of ghrelin is inhibited by insulin, growth hormone (somatotropin), leptin, glucose, glucagon, and fatty acids. Secretion is stimulated by insulin-like growth factor-1 and muscarinic agonists.
In the bloodstream acyl ghrelin is deacylated by butyrylcholinesterase and platelet-activating factor acetylhydrolase. Other enzymes may also deacylate acyl ghrelin. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=422085
Preproghrelin is cleaved to yield proghrelin which is then acylated by ghrelin O-acyltransferase to yield octanoyl ghrelin and decanoyl ghrelin. Only octanoyl ghrelin is able to bind and activate the GHS-R1a receptor. Unacylated ghrelin (des-acyl ghrelin) is also present in plasma but its function is controversial.
Acyl proghrelin is cleaved by prohormone convertase 1/3 to yield the mature acyl ghrelin and C-ghrelin. Secretion of ghrelin is inhibited by insulin, growth hormone (somatotropin), leptin, glucose, glucagon, and fatty acids. Secretion is stimulated by insulin-like growth factor-1 and muscarinic agonists.
In the bloodstream acyl ghrelin is deacylated by butyrylcholinesterase and platelet-activating factor acetylhydrolase. Other enzymes may also deacylate acyl ghrelin. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=422085
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- Marrades MP, Milagro FI, Martínez JA, Moreno-Aliaga MJ.; ''Differential expression of aquaporin 7 in adipose tissue of lean and obese high fat consumers.''; PubMed Europe PMC Scholia
- Padma S, Smeltz AM, Banks PM, Iannitti DA, McKillop IH.; ''Altered aquaporin 9 expression and localization in human hepatocellular carcinoma.''; PubMed Europe PMC Scholia
- Tsukaguchi H, Weremowicz S, Morton CC, Hediger MA.; ''Functional and molecular characterization of the human neutral solute channel aquaporin-9.''; PubMed Europe PMC Scholia
- Maeda N, Hibuse T, Funahashi T.; ''Role of aquaporin-7 and aquaporin-9 in glycerol metabolism; involvement in obesity.''; PubMed Europe PMC Scholia
- Frühbeck G, Catalán V, Gómez-Ambrosi J, Rodríguez A.; ''Aquaporin-7 and glycerol permeability as novel obesity drug-target pathways.''; PubMed Europe PMC Scholia
- Kondo H, Shimomura I, Kishida K, Kuriyama H, Makino Y, Nishizawa H, Matsuda M, Maeda N, Nagaretani H, Kihara S, Kurachi Y, Nakamura T, Funahashi T, Matsuzawa Y.; ''Human aquaporin adipose (AQPap) gene. Genomic structure, promoter analysis and functional mutation.''; PubMed Europe PMC Scholia
- Ohgusu Y, Ohta KY, Ishii M, Katano T, Urano K, Watanabe J, Inoue K, Yuasa H.; ''Functional characterization of human aquaporin 9 as a facilitative glycerol carrier.''; PubMed Europe PMC Scholia
- Elkjaer M, Vajda Z, Nejsum LN, Kwon T, Jensen UB, Amiry-Moghaddam M, Frøkiaer J, Nielsen S.; ''Immunolocalization of AQP9 in liver, epididymis, testis, spleen, and brain.''; PubMed Europe PMC Scholia
- Viadiu H, Gonen T, Walz T.; ''Projection map of aquaporin-9 at 7 A resolution.''; PubMed Europe PMC Scholia
- Kuriyama H, Kawamoto S, Ishida N, Ohno I, Mita S, Matsuzawa Y, Matsubara K, Okubo K.; ''Molecular cloning and expression of a novel human aquaporin from adipose tissue with glycerol permeability.''; PubMed Europe PMC Scholia
- Fain JN, Buehrer B, Bahouth SW, Tichansky DS, Madan AK.; ''Comparison of messenger RNA distribution for 60 proteins in fat cells vs the nonfat cells of human omental adipose tissue.''; PubMed Europe PMC Scholia
- Rojek A, Praetorius J, Frøkiaer J, Nielsen S, Fenton RA.; ''A current view of the mammalian aquaglyceroporins.''; PubMed Europe PMC Scholia
History
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External references
DataNodes
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| Name | Type | Database reference | Comment |
|---|---|---|---|
| 2xHC-INS | Protein | P01308 (Uniprot-TrEMBL)  | |
| 4xHC-INS | Protein | P01308 (Uniprot-TrEMBL) | |
| Acyl Ghrelin | Protein | REACT_20017 (Reactome) | |
| Acyl Ghrelin | Protein | REACT_20031 (Reactome) | |
| Acyl Proghrelin | Protein | REACT_20024 (Reactome) | |
| Butyrylcholinesterase | Protein | REACT_161413 (Reactome) | This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis. |
| Ca2+ | Metabolite | CHEBI:29108 (ChEBI) | |
| DECA | Metabolite | CHEBI:30813 (ChEBI) | |
| DecS-GHRL-1 | Protein | Q9UBU3-1 (Uniprot-TrEMBL) | |
| Des-acyl Ghrelin | Protein | REACT_19664 (Reactome) | |
| FAs | Metabolite | CHEBI:35366 (ChEBI) | |
| GH1 | Protein | P01241 (Uniprot-TrEMBL) | Growth hormone is typically used to refer to the endogenous hormone - somatotropin is reserved for synthetic hormone produced by recombinant technology. |
| GHRL-1 | Protein | Q9UBU3-1 (Uniprot-TrEMBL) | |
| Glc | Metabolite | CHEBI:17925 (ChEBI) | |
| Glucagon | Protein | P01275 (Uniprot-TrEMBL) | |
| IGF1 | Protein | P05019 (Uniprot-TrEMBL) | |
| KLF4 | Protein | O43474 (Uniprot-TrEMBL) | |
| LEP | Protein | P41159 (Uniprot-TrEMBL) | |
| MBOAT4 | Protein | Q96T53 (Uniprot-TrEMBL) | |
| O-octanoyl-L-serine-GHRL-1 | Protein | Q9UBU3-1 (Uniprot-TrEMBL) | |
| Octanoic acid | Metabolite | CHEBI:28837 (ChEBI) | |
| PC1 calcium cofactor | Complex | REACT_17306 (Reactome) | |
| PCSK1 | Protein | P29120 (Uniprot-TrEMBL) | |
| PLA2G7 | Protein | Q13093 (Uniprot-TrEMBL) | |
| Preproghrelin and prepro-des-Gln14-ghrelin | Protein | REACT_19780 (Reactome) | |
| Proghrelin and Pro-des-Gln14-ghrelin | Protein | REACT_19492 (Reactome) | |
| SEC11A | Protein | P67812 (Uniprot-TrEMBL) | |
| SEC11C | Protein | Q9BY50 (Uniprot-TrEMBL) | |
| SPCS1 | Protein | Q9Y6A9 (Uniprot-TrEMBL) | |
| SPCS2 | Protein | Q15005 (Uniprot-TrEMBL) | |
| SPCS3 | Protein | P61009 (Uniprot-TrEMBL) | |
| Signal Peptidase | Complex | REACT_15945 (Reactome) | |
| insulin | Complex | REACT_5828 (Reactome) |
Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| Acyl Ghrelin | Arrow | REACT_19136 (Reactome) | ||
| Acyl Ghrelin | Arrow | REACT_19170 (Reactome) | ||
| Acyl Ghrelin | REACT_19136 (Reactome) | |||
| Butyrylcholinesterase | mim-catalysis | REACT_19294 (Reactome) | ||
| DECA | REACT_19329 (Reactome) | |||
| FAs | TBar | REACT_19136 (Reactome) | ||
| GH1 | TBar | REACT_19136 (Reactome) | ||
| GHRL-1 | Arrow | REACT_19136 (Reactome) | ||
| GHRL-1 | Arrow | REACT_19170 (Reactome) | ||
| GHRL-1 | REACT_19136 (Reactome) | |||
| GHRL-1 | REACT_19318 (Reactome) | |||
| GHRL-1 | REACT_19329 (Reactome) | |||
| Glc | TBar | REACT_19136 (Reactome) | ||
| Glucagon | TBar | REACT_19136 (Reactome) | ||
| IGF1 | Arrow | REACT_19136 (Reactome) | ||
| KLF4 | Arrow | REACT_19166 (Reactome) | ||
| LEP | TBar | REACT_19136 (Reactome) | ||
| MBOAT4 | mim-catalysis | REACT_19318 (Reactome) | ||
| MBOAT4 | mim-catalysis | REACT_19329 (Reactome) | ||
| Octanoic acid | REACT_19318 (Reactome) | |||
| PC1 calcium cofactor | mim-catalysis | REACT_19170 (Reactome) | ||
| PLA2G7 | mim-catalysis | REACT_19294 (Reactome) | ||
| REACT_19136 (Reactome) | Acyl ghrelin and C-ghrelin are secreted from secretory granules into the bloodstream. Five forms of acyl ghrelin have been detected: octanoyl ghrelin-28, decanoyl ghrelin-28, octanoyl ghrelin-27, decanoyl ghrelin-27, and decenoyl ghrelin-28. Unacylated ghrelin (des-acyl ghrelin) occurs at higher levels than acyl ghrelin however its function and mechanism of generation are controversial. The function, if any, of C-ghrelin is also unknown. Secretion of ghrelin is stimulated by insulin-like growth factor-1 and muscarinic agonists; Secretion is inhibited by insulin, somatotropin, leptin, glucose, glucagon, and fatty acids. Carbohydrates have more inhibitory effect than fat does. The mechanisms by which the regulation is effected are unknown. | |||
| REACT_19166 (Reactome) | The ghrelin gene is transcribed and spliced to yield two variants: isoform 1 encodes full-length preproghrelin and isoform 2 encodes des-acyl-Gln14 preproghrelin, which is missing glutamine at position 14 of the mature peptide. Des-acyl-Gln14 ghrelin is found in rodents but is present in negligible quantities in humans. Somatostatin and leptin inhibit ghrelin mRNA levels. Estrogen increases ghrelin mRNA levels. The KLF4 transcription factor binds the ghrelin promoter and activates transcription. Putative binding sites for other transcription factors have been identified but their functions have not been demonstrated. | |||
| REACT_19170 (Reactome) | Acyl proghrelin is cleaved by prohormone convertase 1/3 (PC1/3) to yield acyl ghrelin (the N-terminal fragment) and C-ghrelin (the C-terminal fragment). Transfection experiments show that PC1/3 is sufficient to generate acyl ghrelin of 28 amino acid residues (acyl ghrelin-28). Acyl ghrelin of 27 amino acid residues (acyl ghrelin-27) can also be detected in plasma. How acyl ghrelin-27 is generated remains undetermined but it is speculated to derive from the cleavage of arginine-28 from the C-terminus of ghrelin by a carboxypeptidase B-like enzyme. | |||
| REACT_19294 (Reactome) | The majority of circulating ghrelin is not acylated (des-acyl ghrelin). Acyl ghrelin can be deacylated in the bloodstream by butyrylcholinesterase and platelet-activating factor acetylhydrolase, which are associated with circulating lipids. Other enzymes may also have this capability. It is unknown if a portion of des-acyl ghrelin in the bloodstream is generated by direct synthesis and secretion. | |||
| REACT_19296 (Reactome) | The N-terminal 23 amino acid residues are cleaved from preproghrelin by the signal peptidase complex. The products are proghrelin (94 amino acid residues) or des-acyl-Gln14 proghrelin (93 amino acid residues), depending on the variant of the mRNA that was translated. | |||
| REACT_19318 (Reactome) | Proghrelin is octanoylated by ghrelin O-acyltransferase (GOAT/MBOAT4), an enzyme present in the endoplasmic reticulum membrane which both transports the octanoic acid substrate and condenses it on the hydroxyl group of serine-3 of the mature protein. The most common acylated form of ghrelin is octanoyl ghrelin but decanoyl ghrelin is also detected. Ghrelin is the only protein known to undergo such a modification. | |||
| REACT_19329 (Reactome) | Proghrelin is decanoylated by ghrelin O-acyltransferase (GOAT/MBOAT4), an enzyme present in the endoplasmic reticulum membrane which both transports the decanoic acid substrate and condenses it on the hydroxyl group of serine-3 of the mature protein. The most common acylated form of ghrelin is octanoyl ghrelin but decanoyl ghrelin is also detected in plasma. GOAT is able to use substrates up to tetradecanoic acid. Ghrelin is the only protein known to undergo such a modification. | |||
| Signal Peptidase | mim-catalysis | REACT_19296 (Reactome) | ||
| insulin | TBar | REACT_19136 (Reactome) |
