Fetuin

fetuin-B
fetuin-B
Identifiers
Symbol	FETUB
Alt. symbols	16G2, Gugu
NCBI gene	26998
HGNC	3658
OMIM	605954
RefSeq	NM_014375
UniProt	Q9UGM5
Other data
Locus	Chr. 3 q27.3
Structures
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Structures	Swiss-model
Domains	InterPro

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Structures	Swiss-model
Domains	InterPro

Α2-HS-glycoprotein
Α2-HS-glycoprotein
Identifiers
Symbol	AHSG
Alt. symbols	FETUA, A2HS, HSGA
NCBI gene	197
HGNC	349
OMIM	138680
RefSeq	NM_001622
UniProt	P02765
Other data
Locus	Chr. 3 q27.3
Structures
Search for
Structures	Swiss-model
Domains	InterPro

Last updated November 23, 2024

X-ray picture of a Fetuin-A knockout mouse (-/-) compared to a wildtype mouse (+/+). The bright dots in the fetuin-A deficient mouse indicate calcified lesions throughout the body. FetuinAKnockout.jpg — X-ray picture of a Fetuin-A knockout mouse (-/-) compared to a wildtype mouse (+/+). The bright dots in the fetuin-A deficient mouse indicate calcified lesions throughout the body.

Fetuins are blood proteins that are made in the liver and secreted into the bloodstream. They belong to a large group of binding proteins mediating the transport and availability of a wide variety of cargo substances in the bloodstream.^[1] Fetuin-A is a major carrier protein of free fatty acids in the circulation.^[1] The best known representative of carrier proteins is serum albumin,^{[ citation needed ]} the most abundant protein in the blood plasma of adult animals. Fetuin is more abundant in fetal blood, hence the name "fetuin" (from Latin, fetus). Fetal bovine serum contains more fetuin than albumin, while adult serum contains more albumin than fetuin.

Family members

Human fetuin is synonymous with α2-HS-glycoprotein (genetic symbol AHSG), α2-HS, A2HS, AHS, HSGA, and fetuin-A. Fetuin-A exists as a single-copy gene in the human and mouse genomes. A closely related gene, fetuin-B, also exists in the human, rat, and mouse genomes. Like fetuin-A, fetuin-B is made predominantly by the liver and to a lesser extent by a number of secretory tissues. Fetuins exist in all vertebrate genomes including fish and reptiles. Fetuins are members of a family of proteins that evolved from the protein cystatin by gene duplication and exchange of gene segments. Fetuins thus belong to the cystatin superfamily of proteins. Fetuin relatives within this superfamily are the histidine-rich glycoprotein (HRG) and kininogen (KNG).

Animal studies

The function of Fetuin-A in the body was determined by gene knockout technology in mice. Knocking out the gene for fetuin-A rendered the mice completely fetuin-A deficient. Feeding a mineral-rich diet to fetuin-A-deficient mice resulted in widespread calcification (ectopic mineralization) of lung, heart, and kidneys in these mice. The calcification became drastically exacerbated when the fetuin-A knockout was combined with the genetic background DBA/2. The mouse strain DBA/2 is known for its proneness to calcify damaged tissues, a process called "dystrophic calcification". Fetuin-A deficiency dramatically increased the calcification proneness of these mice in that all mice spontaneously calcified throughout their body even without a mineral-rich diet or surgical tissue trauma. Fetuin-A is therefore regarded as a potent inhibitor of systemic calcification.

Free fatty acids cause Fetuin-A overexpression by increasing the pro-inflammatory protein NF-κB.^[1] Fetuin-A has been shown to facilitate the binding of free fatty acids to TLR4 receptors, thereby inducing insulin resistance in mice.^[1]

Human studies

Fetuin-A was originally discovered to be an inhibitor of vascular calcification in early 1990s. Since then many more roles have been attributed to fetuin-A. Fetuin-A has been demonstrated to play an important role in free fatty acid induced insulin resistance in the liver. Increased fetuin-A in patients with pre-diabetes is associated with increased progression to diabetes and decreased reversal to normoglycemia. Hence fetuin-A is a predictor of adverse glycemic outcomes in pre-diabetes.^[2]^{[ unreliable medical source ]} Obese persons have elevated circulating Fetuin-A, which can be reduced by metformin, exercise, or weight loss. ^[3] Increased fetuin-A has also been linked to increased occurrence of non-alcoholic fatty liver disease and cardiovascular events, believed to be due to its proinflammatory effects.^[4]

Fetuin-A in contrast has also been demonstrated to have anti-inflammatory properties. It is a negative acute-phase reactant in sepsis and endotoxemia, promotes wound healing, and is neuroprotective in Alzheimer's disease. Decreased fetuin-A is a predictor of increased disease activity in obstructive lung disease, Crohn's disease, and ulcerative colitis. Differential effects on different toll like receptors in different tissues and organ systems may explain these paradoxical effects in different systems.^[5]^{[ unreliable medical source ]}

Related Research Articles

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Transferrins are glycoproteins found in vertebrates which bind and consequently mediate the transport of iron (Fe) through blood plasma. They are produced in the liver and contain binding sites for two Fe³⁺ ions. Human transferrin is encoded by the TF gene and produced as a 76 kDa glycoprotein.

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro, and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).

Adiponectin is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain.

Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.

Serum albumin, often referred to simply as blood albumin, is an albumin found in vertebrate blood. Human serum albumin is encoded by the ALB gene. Other mammalian forms, such as bovine serum albumin, are chemically similar.

Human serum albumin is the serum albumin found in human blood. It is the most abundant protein in human blood plasma; it constitutes about half of serum protein. It is produced in the liver. It is soluble in water, and it is monomeric.

<span class="mw-page-title-main">Calciphylaxis</span> Painful, necrotic skin lesions associated with chronic kidney disease

Calciphylaxis, also known as calcific uremic arteriolopathy (CUA) or “Grey Scale”, is a rare syndrome characterized by painful skin lesions. The pathogenesis of calciphylaxis is unclear but believed to involve calcification of the small blood vessels located within the fatty tissue and deeper layers of the skin, blood clots, and eventual death of skin cells due to lack of blood flow. It is seen mostly in people with end-stage kidney disease but can occur in the earlier stages of chronic kidney disease and rarely in people with normally functioning kidneys. Calciphylaxis is a rare but serious disease, believed to affect 1-4% of all dialysis patients. It results in chronic non-healing wounds and indicates poor prognosis, with typical life expectancy of less than one year.

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

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Free Fatty acid receptor 4 (FFAR4), also termed G-protein coupled receptor 120 (GPR120), is a protein that in humans is encoded by the FFAR4 gene. This gene is located on the long arm of chromosome 10 at position 23.33. G protein-coupled receptors reside on their parent cells' surface membranes, bind any one of the specific set of ligands that they recognize, and thereby are activated to trigger certain responses in their parent cells. FFAR4 is a rhodopsin-like GPR in the broad family of GPRs which in humans are encoded by more than 800 different genes. It is also a member of a small family of structurally and functionally related GPRs that include at least three other free fatty acid receptors (FFARs) viz., FFAR1, FFAR2, and FFAR3. These four FFARs bind and thereby are activated by certain fatty acids.

alpha-2-HS-glycoprotein also known as fetuin-A is a protein that in humans is encoded by the AHSG gene. Fetuin-A belongs to the fetuin class of plasma binding proteins and is more abundant in fetal than adult blood.

Amine oxidase, copper containing 3 (AOC3), also known as vascular adhesion protein (VAP-1) and HPAO is an enzyme that in humans is encoded by the AOC3 gene on chromosome 17. This protein is a member of the semicarbazide-sensitive amine oxidase family of enzymes and is associated with many vascular diseases.

FABP1 is a human gene coding for the protein product FABP1. It is also frequently known as liver-type fatty acid-binding protein (LFABP).

Leukocyte cell-derived chemotaxin-2 (LECT2) is a protein first described in 1996 as a chemotactic factor for neutrophils, i.e. it stimulated human neutrophils to move directionally in an in vitro assay system. The protein was detected in and purified from cultures of Phytohaemagglutinin-activated human T-cell leukemia SKW-3 cells. Subsequent studies have defined LECT2 as a hepatokine, i.e. a substance made and released into the circulation by liver hepatocyte cells that regulates the function of other cells: it is a hepatocyte-derived, hormone-like, signaling protein.

Fetuin-B is a protein that in humans is encoded by the FETUB gene.

<span class="mw-page-title-main">Lipotoxicity</span> Metabolic disorder in which lipids accumulate in non-fat tissue

Lipotoxicity is a metabolic syndrome that results from the accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death. The tissues normally affected include the kidneys, liver, heart and skeletal muscle. Lipotoxicity is believed to have a role in heart failure, obesity, and diabetes, and is estimated to affect approximately 25% of the adult American population.

Hepatokines are proteins produced by liver cells (hepatocytes) that are secreted into the circulation and function as hormones across the organism. Research is mostly focused on hepatokines that play a role in the regulation of metabolic diseases such as diabetes and fatty liver and include: Adropin, ANGPTL4, Fetuin-A, Fetuin-B, FGF-21, Hepassocin, LECT2, RBP4,Selenoprotein P, Sex hormone-binding globulin.

References

1 2 3 4 Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S (2012). "Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance" (PDF). Nature Medicine . 18 (8): 1279–1285. doi:10.1038/nm.2851. PMID 22842477. S2CID 888828. Archived from the original (PDF) on 2018-09-07. Retrieved 2018-09-07.
↑ Dutta D, Mondal SA, Kumar M, Hasanoor Reza AH, Biswas D, Singh P, Chakrabarti S, Mukhopadhyay S (2014). "Serum fetuin-A concentration predicts glycaemic outcomes in people with prediabetes: a prospective study from eastern India". Diabet. Med. 31 (12): 1594–9. doi: 10.1111/dme.12539 . PMID 24975463. S2CID 8532064.
↑ Trepanowski JF, Mey J, Varady KA (2015). "Fetuin-A: a novel link between obesity and related complications". International Journal of Obesity . 39 (5): 734–741. doi:10.1038/ijo.2014.203. PMID 25468829. S2CID 24089111.
↑ Nascimbeni F, Romagnoli D, Ballestri S, Baldelli E, Lugari S, Sirotti V, Giampaoli V, Lonardo A (2018). "Do Nonalcoholic Fatty Liver Disease and Fetuin-A Play Different Roles in Symptomatic Coronary Artery Disease and Peripheral Arterial Disease?". Diseases. 6 (1): E17. doi: 10.3390/diseases6010017 . PMC 5871963 . PMID 29462898.
↑ Mukhopadhyay S, Mondal SA, Kumar M, Dutta D (2014). "Proinflammatory and antiinflammatory attributes of fetuin-a: a novel hepatokine modulating cardiovascular and glycemic outcomes in metabolic syndrome". Endocr Pract. 20 (12): 1345–51. doi:10.4158/EP14421.RA. PMID 25370330.