Leukocyte cell-derived chemotaxin-2 (LECT2) is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
first described in 1996 as a
chemotactic factor
Chemotaxis (from '' chemo-'' + ''taxis'') is the movement of an organism or entity in response to a chemical stimulus. Somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemica ...
for
neutrophils
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
, i.e. it stimulated human neutrophils to move directionally in an
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
assay system. The protein was detected in and purified from cultures of
Phytohaemagglutinin
Phytohaemagglutinin (PHA, or phytohemagglutinin) is a lectin found in plants, especially certain legumes. PHA actually consists of two closely related proteins, called leucoagglutinin (PHA-L) and PHA-E. These proteins cause blood cells to clump ...
-activated human T-cell leukemia SKW-3 cells.
Subsequent studies have defined LECT2 as a
hepatokine Hepatokines (Greek ''heapto-'', liver; and ''-kinos'', movement) 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 ...
, i.e. a substance made and released into the circulation by liver
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
cells that regulates the function of other cells: it is a hepatocyte-derived,
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
-like, signaling protein.
LECT2 has been detected in the blood and other tissues in a wide range of animal species from
zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family ( Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ...
to man. Furthermore, its levels in these tissues often change as a function of various diseases. These findings indicate that LECT is an evolutionary conserved protein, has one or more important functions, and may be involved in various diseases. However, LECT2's relationships to these diseases requires much further study before they can be regarded as established and clinically useful. One exception to this, however, is its proven role in
amyloidosis
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weight ...
. LECT2 is one of the more common causes of systemic (as opposed to localized) amyloidosis in North America as well as certain other ethnically-rich locations.
LECT2 and its gene, ''LECT2'', are currently areas of active research that seek to implicate them as contributors to,
markers for the presence of, and/or prognostic indicators for the severity of not only amyloidosis but also
osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
,
rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
, and other types of
inflammation
Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
-related disorders; the
metabolic syndrome
Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).
Metabolic syndrome ...
and
diabetes
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
; and various types of liver disease.
Gene
The human LECT2 gene, ''LECT2'', is located on the long, i.e, "q", arm of chromosome 5 at position q31.1 (notated as 5q31.1). This location is close to several immune modulating genes including
interleukin
Interleukins (ILs) are a group of cytokines (secreted proteins and signal molecules) that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related ...
s 3, 5, and 9 and
granulocyte-macrophage colony stimulating factor
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, natural killer cells, endothelial cells and fibroblasts ...
. ''LECT2'' is conserved in zebrafish, chicken, rat, mouse, cow. dog, Rhesus monkey, and chimpanzee. Human ''LECT2'' is composed of 4
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
, 3
introns
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
, and ~8,000
base pair
A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s. The gene has numerous
single nucleotide variant
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
s as well as other variations, some of which have been associated with human disease. Human ''LECT2'' has several different
transcriptional initiation
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules called ...
sights and codes for a
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
composed of 1,000 to 1,300
ribonucleotide
In biochemistry, a ribonucleotide is a nucleotide containing ribose as its pentose component. It is considered a molecular precursor of nucleic acids. Nucleotides are the basic building blocks of DNA and RNA. Ribonucleotides themselves are basic m ...
s. mRNA for LECT2 is highly expressed in liver tissue and expressed at far lower levels in a wide range of other tssues.
Protein
Human LECT2 is a secreted, 16
kilodalton
The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at ...
protein. The secreted protein consists of 133`
amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
(mouse Lect2 consists of two varieties a typical 151 amino acid protein and an atypical 132 amino acid protein). Its structure is similar to that of the M23 family of
metalloendopeptidase A metalloendopeptidase is an enzyme that functions as a metalloproteinase endopeptidase
Endopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acids (i.e. within the molecule), in contrast to exopep ...
s. Unlike this family of peptidases, however, LECT2 has not been found to possess enzymatic activity and does not appear to share any functions with M23 metalloendopeptidases.
LECT2 protein is widely expressed in vascular tissues,
smooth muscle cells
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
,
adipocytes
Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
, cerebral
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s, apical
squamous epithelia
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
,
parathyroid
Parathyroid glands are small endocrine glands in the neck of humans and other tetrapods. Humans usually have four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes par ...
tissues, the
epithelial cells
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
of
sweat
Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals.
Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distribut ...
and
sebaceous gland
A sebaceous gland is a microscopic exocrine gland in the skin that opens into a hair follicle to secrete an oily or waxy matter, called sebum, which lubricates the hair and skin of mammals. In humans, sebaceous glands occur in the greatest number ...
s, Hassall bodies, and
monocytes
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also infl ...
. When these cells or tissues are subjected to inflammatory, fibrotic, and other insults, they commonly reduce their expression of LECT2. The liver
hepatocyte
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
is considered to be the source of the LECT2 circulating in blood. However, its expression in these cells is extremely low or undetectable even though these cells express very high levels of LECT2 mRNA. This implies that hepatocytes secrete LECT2 almost immediately after they make it. Using very sensitive methods, LECT2 protein can also be detected at low levels in the endothelial cells of hepatic arteries and veins including
central veins. Several cell types or tissues, e.g.
osteoblasts
Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
,
chondrocytes
Chondrocytes (, from Greek χόνδρος, ''chondros'' = cartilage + κύτος, ''kytos'' = cell) are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteog ...
, cardiac tissue, gastrointestinal
smooth muscle cells
Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
, and epithelial cells of some tissues normally do not express LECT2 but do so under a variety of disease conditions.
Disease associations
LECT2 amyloidosis
LECT2 amyloidosis (ALECT2) was the third most common (~3% of total) cause of amyloidosis in a series of >4,000 individuals studied at the
Mayo Clinic
The Mayo Clinic () is a nonprofit American academic medical center focused on integrated health care, education, and research. It employs over 4,500 physicians and scientists, along with another 58,400 administrative and allied health staff, ...
in the United States. However, LECT2 amyloidosis has a strong ethnic bias, afflicting particularly Mexicans and to a lesser extent, non-Mexican Hispanics. Hispanics made an important contribution to the Mayo Clinic's rate of LECT2 amyloidosis. LECT2 amyloidosis also has an increased incidence in Punjabis, South Asians,
First Nations
First Nations or first peoples may refer to:
* Indigenous peoples, for ethnic groups who are the earliest known inhabitants of an area.
Indigenous groups
*First Nations is commonly used to describe some Indigenous groups including:
**First Natio ...
people of British Columbia, Native Americans, and Egyptians. In Egyptians, LECT2 is second most common cause of renal amyloidosis, accounting for nearly 31% of all cases. LECT2 amyloidosis is likely to be a far less common cause of systemic amyloidosis in populations containing fewer numbers of individuals of the cited ethnic groups.
On the other hand, LECT2 amyloidosis represents an important but at present very much under-recognized cause of chronic kidney disease in the cited ethnic groups and, possibly, other ethnic groups yet to be determined.
It has been found repeatedly that the mere presence of LECT2
amyloid
Amyloids are aggregates of proteins characterised by a Fibril, fibrillar morphology of 7–13 Nanometer, nm in diameter, a beta sheet (β-sheet) Secondary structure of proteins, secondary structure (known as cross-β) and ability to be Staining, ...
tissue deposits does not necessarily indicate the presence of LECT2 amyloidosis disease. For example,
autopsy
An autopsy (post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of death or to evaluate any di ...
studies find that up to 3.1% of Hispanics have these deposits in their kidneys but no history of signs or symptoms that could be attributed to LECT2 amyloidosis. This finding suggests that the LECT2 amyloidosis and its ethnic bias reflect multiple poorly understood factors.
Pathophysiology
While the pathogenesis of LECT2 amyloidosis is unclear, the intact LECT2 protein may have a tendency to fold abnormally thereby forming non-soluble fibrils that are deposited in tissues. It has been suggested that individuals with the disease have an increase in LECT2 production and/or a decrease in LECT2
catabolism
Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipids, ...
(i.e. breakdown) which leads to its tissue deposition. However, there appears to be clear genetic variations that lead LECT2 tissue deposition. While studies to date have failed to obtain evidence for ''LECT2'' gene mutations in the disorder, most cases examined in the United States are associated with a particular
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
single nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
(i.e. SNP) in the ''LECT2'' gene. This SNP occurs in exon 3 at
codon
The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
58 of the gene, contains a
guanine
Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
rather than
adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...
nucleotide
Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
at this site, and consequently codes for the amino acid
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotonat ...
rather than
isoleucine
Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the deprot ...
. It is suggested although not yet proven that this Val58Ile variant of LECT2 has a propensity to fold abnormally and therefore deposits in tissues. The Val58Ile LECT2 variant is common in Hispanics and appears to be the cause of their high incidence of LECT2 amyloidosis. Nonetheless, not all homozygous carriers of the variant ever exhibit LECT2 amyloidosis.
A second SNP commonly found in Mexicans occurs at codon 172 of the ''LECT2 gene''. This variant is homozygous for a G nucleotide at this codon position and has been associated with an increased incidence of LECT2 amyloidosis. A reason for this association has not yet been proposed.
Presentation
LECT2 amyloidosis presents with renal disease that in general is slowly progressive and at the time of presentation is of varying severity ranging from early findings of
proteinuria
Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom ma ...
or small elevations in
blood urea nitrogen
Blood urea nitrogen (BUN) is a medical test that measures the amount of urea nitrogen found in blood. The liver produces urea in the urea cycle as a waste product of the digestion of protein. Normal human adult blood should contain 6 to 20 mg/dL ...
and/or
creatinine
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an import ...
to findings of
end stage renal disease
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
. At presentation, many individuals are elderly and suffer serious kidney dysfunction. They may have histological evidence of LECT2 amyloid deposition in the liver, lung, spleen, kidney, and adrenal glands of rarely show any symptoms or signs attributable to dysfunction in these organs. Unlike many other forms of systemic amyloidosis, LECT2 deposition has not been reported to be deposited in the myocardium or brain of afflicted individuals. Thus, LECT2 amyloidosis, while classified as a form of systemic amyloidosis, is almost exclusively manifested clinically as renal amyloidosis.
Diagnosis
LECT amyloidosis is diagnosed by two findings: a) histological evidence of
Congo red
Congo red is an organic compound, the sodium salt of 3,3′-( ,1′-biphenyl4,4′-diyl)bis(4-aminonaphthalene-1-sulfonic acid). It is an azo dye. Congo red is water-soluble, yielding a red colloidal solution; its solubility is greater in organic ...
staining material deposited in the interstitial, mesangial, glomerular, and/or vascular areas of the kidney and b) the identification of these deposits as containing mainly LECT2 as identified by
proteomics
Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In ...
methodologies. Kidney biopsy shows the presence of LECT2-based amyloid predominantly in the renal cortex interstitium, glomeruli, and arterioles.
Treatment
There Is too little experience on the treatment of LECT2 amyloidosis (ALECT2) to establish recommendations. There is no recommended specific treatment for LECT2 amyloidosis other than support of kidney function and
dialysis Dialysis may refer to:
*Dialysis (chemistry), a process of separating molecules in solution
**Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric pote ...
. It is important to accurately diagnose ALECT2-based amyloid disease in order to avoid treatment for other forms of amyloidosis.
Prognosis
Based on studies conducted in the United States, the prognosis for individuals with LECT2 amyloidosis is guarded, particularly because they are elderly and their kidney disease is usually well-advanced at the time of presentation.
Rheumatoid arthritis
Studies conducted in a mouse model of rheumatoid arthritis indicate that the LECT2 protein suppresses the inflammatory component of this disorder. In human studies, the Val58Ile variant of LECT2 protein which has been associated with the development of LECT2 amyloidosis in Hispanics has also been associated with rheumatoid arthritis. That is, individuals
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for the gene making the Val58Ile variant of LECT2 have a small but significant increase in both the incidence and severity of this disease based on a study conducted in Japan. An increase in the severity and joint destruction of rheumatoid arthritis in humans was confirmed in a separate study conducted in Germany. These studies suggest that LECT2 normally functions to suppress the development and/or severity of human rheumatoid arthritis and that the Val58Ile variant of LECT2 is less effective in doing so.
Osteoarthritis
In a model of
osteoarthritis
Osteoarthritis (OA) is a type of degenerative joint disease that results from breakdown of joint cartilage and underlying bone which affects 1 in 7 adults in the United States. It is believed to be the fourth leading cause of disability in the w ...
, mice made deficient in LECT2 using a
gene knockout
A gene knockout (abbreviation: KO) is a genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the gene kno ...
method developed more severe osteoarthritis induced by anti-type II collagen antibodies and
lipopolysaccharide
Lipopolysaccharides (LPS) are large molecules consisting of a lipid and a polysaccharide that are bacterial toxins. They are composed of an O-antigen, an outer core, and an inner core all joined by a covalent bond, and are found in the outer m ...
. The effect was reversed by administering human LECT2 to the animals. A study conducted in Japan found that the expression levels of LECT2 were significantly higher in cartilage of osteoarthritic individuals than in control patients suggesting that LECT2 may be a useful biomarker for the disease.
Sepsis
In mouse models of bacterial sepsis caused by of
E. coli
''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
,
P. aeruginosa P. is an abbreviation or acronym that may refer to:
* Page (paper), where the abbreviation comes from Latin ''pagina''
* Paris Herbarium, at the ''Muséum national d'histoire naturelle''
* ''Pani'' (Polish), translating as Mrs.
* The ''Pacific Repo ...
, and ligation followed by puncture of the cecum, the administration of human LECT2 improved survival. LECTT2 acted by directly stimulating the
CD209
DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) also known as CD209 (cluster of differentiation, Cluster of Differentiation 209) is a protein which in humans is encoded by the ''CD209'' gene.
DC-SIGN is ...
receptor on mouse macrophages thereby mobilizing their protective functions. Knockout of the ''Lect2'' gene in mice increase the mortality caused by staphylococcal
enterotoxin
An enterotoxin is a protein exotoxin released by a microorganism that targets the intestines.
Enterotoxins are chromosomally encoded or plasmid encoded exotoxins that are produced and secreted from several bacterial organisms. They are heat labi ...
A; human LECT2 reduced this morality increase. Blood levels of LECT2 in patients suffering bacterial sepsis correlated inversely with the severity of systemic inflammation suggesting that LECT2 blood levels may be a reliable diagnostic indicator of human inflammatory diseases.
Diabetes
Deletion of the ''Lect2'' gene in mice improves peripheral glucose entry into tissues. These studies suggest that mouse Lect2 suppresses insulin signaling in skeletal muscle but not adipose or liver tissues of Lect2-deficient mice and thereby may contribute to the development of
insulin resistance
Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
. Indeed, serum levels of LECT2 are increased in animal models of insulin-resistant diabetes as well as in individual diabetics demonstrating insulin resistance. These data suggest that inhibiting LECT2 production or action may be clinically useful means for treating diabetes.
In support of this notion,
Gemigliptin
Gemigliptin (rINN), sold under the brand name Zemiglo, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the dipeptidyl peptidase-4 inhibitor (DPP-4 inhibitor) class of drugs. Glucose lowering effects of DPP-4 inhibitors are mainly med ...
, an anti-diabetic drug, has been shown reduce insulin resistance and concurrently inhibit Lect2 production in a mouse model of dietary-induces insulin resistance.
Studies conducted on cultured
myocytes
A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a muscl ...
, a form of muscle cell, indicates that LECT2 impairs insulin signaling by activating a
c-Jun N-terminal kinases
c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are res ...
cell signaling pathway.
Metabolic syndrome
Mice made deficient in the ''Lect2'' gene were compared to wild-type mice in a model of high fatty acid diet-induced obesity and the
metabolic syndrome
Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).
Metabolic syndrome ...
. ''Lect2''-deficient mice appeared to be protected from developing certain characteristics of the metabolic syndrome: they exhibited less weight gain; lower blood glucose and insulin levels following feeding; and better results for
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
and
insulin tolerance test
An insulin tolerance test (ITT) is a medical diagnostic procedure during which insulin is injected into a patient's vein, after which blood glucose is measured at regular intervals. This procedure is performed to assess pituitary function, adrenal ...
s. In a study of 200 individuals in Japan, serum LECT2 levels correlated positively with (i.e. increased in proportion to increases in) several clinical features of the
metabolic syndrome
Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).
Metabolic syndrome ...
viz.,
body mass index
Body mass index (BMI) is a value derived from the mass (weight) and height of a person. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of kg/m2, resulting from mass in kilograms and he ...
, waist circumference,
systolic blood pressure
Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
,
selenoprotein P
In molecular biology, the protein domain selenoprotein P (SelP) is the only known eukaryotic selenoprotein that contains multiple selenocysteine (Sec) residues. It is a secreted glycoprotein, often found in the plasma. Its precise function remain ...
serum levels, and
hemoglobin A1c
Glycated hemoglobin, also known as HbA1c, glycohemoglobin, hemoglobin A1c, A1C, is a form of hemoglobin (Hb) that is chemically linked to a sugar. Most monosaccharides, including glucose, galactose and fructose, spontaneously (i.e. non-enzymat ...
blood levels.
Levels of LECT2 are also elevated in individuals not only with diagnosed metabolic syndrome but also with a characteristic of and possible precursor to the metabolic syndrome,
non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
.
LEPT2 has been suggested to be a potential therapeutic target for treating the metabolic syndrome.
Cancer
Circulating levels of LECT2 are elevated in >90% of individuals with
hepatoblastoma
Hepatoblastoma is a malignant liver cancer occurring in infants and children and composed of tissue resembling fetal liver cells, mature liver cells, or bile duct cells. They usually present with an abdominal mass. The disease is most commonly di ...
and >20% of individuals with
Hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.
It occurs in t ...
. In the latter form of liver cancer, LECT2 levels increase with increasingly poor prognostic stages of the disease and therefore may prove to be valuable prognostic markers.
References
Further reading
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