Birdman protein, also known as BIRD-2 or CREB3L2, is a protein that plays an important role in regulating lipid metabolism and insulin sensitivity. It gets its name from being highly expressed in avian species like chickens and quails. But where exactly does this important protein come from in the human body?
What is Birdman Protein?
Birdman protein is a transcription factor that belongs to the CREB/ATF family of basic leucine zipper (bZIP) proteins. It is encoded by the CREB3L2 gene in humans. Birdman is highly expressed in the liver and adipose tissue, where it regulates the expression of genes involved in lipid metabolism.
Some key facts about birdman protein:
- Human birdman protein is 364 amino acids long.
- Molecular weight of approximately 40 kDa.
- Contains a transmembrane domain, bZIP domain, and transcriptional activation domain.
- Expressed in the cytoplasm and nucleus of cells.
- Regulates expression of genes involved in lipogenesis, fat storage, gluconeogenesis, and insulin sensitivity.
By regulating these important metabolic processes, birdman helps control lipid and glucose homeostasis in the body. It is considered an important regulator of metabolism and energy balance.
Birdman Gene and Expression
The CREB3L2 gene encoding birdman protein is located on human chromosome 7 at position 7q33.
This gene contains 13 exons which code for the 364 amino acid birdman protein. Alternative splicing of the CREB3L2 gene results in additional isoforms of the protein also being produced.
Birdman is highly expressed in the following tissues:
- Liver – Hepatocytes produce large amounts of birdman.
- Adipose tissue – Birdman is expressed in both white and brown fat.
- Small intestine – Expressed in enterocytes of the villi.
- Kidney – Birdman is expressed in the tubules.
- Lungs – Present in alveolar cells.
Expression of birdman is controlled by several transcriptional regulators. The hepatocyte nuclear factors HNF-4α and PPARα induce CREB3L2 gene transcription, while SREBP-1c suppresses it. Birdman expression is also induced in the fasted state or with consumption of polyunsaturated fatty acids.
Birdman Synthesis and Processing
Like other proteins in the CREB/ATF family, birdman is synthesized as an inactive transmembrane precursor protein on the endoplasmic reticulum (ER).
The newly translated protein contains several key domains:
- N-terminal transmembrane domain – anchors protein in ER membrane
- Lumenal domain – resides inside the ER lumen
- Cytosolic bZIP domain – binds DNA when released
- C-terminal transactivation domain – involved in activating gene expression
Inside the ER lumen, the lumenal domain senses ER stress signals or deprivation of key metabolites like glucose or lipids. This triggers proteolytic cleavage of the lumenal domain by proteases like S1P and S2P.
This releases the cytosolic portion of birdman from the ER membrane. The protein then translocates to the nucleus where the bZIP domain binds regulatory elements in target genes involved in lipid metabolism and insulin sensitivity.
Birdman Protein Function
As a transcription factor, birdman regulates the expression of many genes involved in lipid metabolism. Some of its main target genes include:
- ACSL5 – Long-chain fatty acid activation
- ELOVL6 – Fatty acid elongation
- FASN – Fatty acid synthesis
- SCD1 – Mono-unsaturated fat production
- PLIN2 – Lipid droplet coating protein
- PCK1 – Gluconeogenesis enzyme
By regulating these critical metabolic genes, birdman protein controls:
- Lipid synthesis and storage in the liver and adipose tissue
- Release of fatty acids through lipolysis
- Glucose production through gluconeogenesis
- Insulin sensitivity and glucose uptake into tissues
When birdman levels are reduced, there is decreased lipid storage and reduced insulin sensitivity. Elevated birdman increases fat accumulation and may contribute to insulin resistance.
In the liver, birdman integrates metabolic signals like glucagon, ER stress, and nutritional deprivation to dynamically regulate lipid and glucose homeostasis during fasting and feeding cycles.
Relevance to Metabolic Disease
Dysregulation of birdman protein is associated with several metabolic disorders including:
- Insulin resistance – Overexpression of birdman induces insulin resistance in mouse models.
- Non-alcoholic fatty liver disease – Birdman levels elevated in human NAFLD patients.
- Hepatic steatosis – Birdman knockout mice protected from fatty liver.
- Obesity – Increased birdman in adipose tissue of obese subjects.
- Type 2 diabetes – Polymorphisms in CREB3L2 linked to increased T2D risk.
Pharmacological inhibitors of birdman are being investigated as potential therapies for treating metabolic disease. Lowering aberrantly elevated birdman activity could help ameliorate insulin resistance, fatty liver, and dyslipidemia.
Conclusion
In summary, birdman protein gets its name from its high expression in birds but plays crucial metabolic roles in humans as well. It is encoded by the CREB3L2 gene and expressed in key metabolic tissues like the liver, fat, and intestine. Birdman is synthesized as a transmembrane ER protein but cleaved and activated in response to metabolic cues. It functions as a transcription factor regulating genes involved in lipid synthesis, storage, and breakdown along with gluconeogenesis. Dysregulation of birdman is linked to several metabolic disorders, highlighting it as a potential therapeutic target.