ANGPTL8 is a protein involved in several fundamental bodily processes. Its discovery has advanced understanding of how the body manages energy and maintains health. Research continues to uncover its diverse roles, highlighting its significance in various physiological and pathological states.
What is ANGPTL8?
ANGPTL8 stands for Angiopoietin-like protein 8, encoded by the ANGPTL8 gene (C19orf80 in humans). It is also known by aliases such as betatrophin, lipasin, RIFL (refeeding-induced fat and liver protein), and TD26. ANGPTL8 is a member of the angiopoietin-like (ANGPTL) protein family, which includes eight proteins (ANGPTL1-8) structurally similar to angiopoietins.
Unlike most other ANGPTL family members, ANGPTL8 lacks the C-terminal fibrinogen-like domain. This differentiates it from ANGPTL1-7, which typically contain this domain. Despite this structural difference, ANGPTL8 retains functional similarities with ANGPTL3 and ANGPTL4, influencing triglyceride metabolism. Human ANGPTL8 is a 22 kDa glycoprotein composed of 198 amino acids, predominantly expressed and secreted by the liver.
Its Primary Role in Metabolism
ANGPTL8 plays a role in both lipid and glucose metabolism, particularly in regulating triglyceride levels. Its primary mechanism involves interacting with ANGPTL3 to inhibit lipoprotein lipase (LPL) activity. LPL is an enzyme that breaks down triglycerides in very-low-density lipoproteins (VLDL) and chylomicrons into fatty acids, which tissues can then absorb.
When ANGPTL8 forms a complex with ANGPTL3, this complex efficiently suppresses LPL activity, leading to reduced clearance of triglycerides from the bloodstream. This inhibition results in elevated circulating triglyceride levels, influencing how the body processes and stores fats. This action is particularly relevant in the post-meal state, where ANGPTL8 directs fatty acids towards adipose tissue for storage.
ANGPTL8 also impacts glucose homeostasis. It influences insulin sensitivity and glucose uptake, though the precise mechanisms are still being explored. ANGPTL8 may improve insulin sensitivity and inhibit hepatic glucose production, contributing to glucose regulation.
ANGPTL8’s Broader Impact on Health
Circulating levels of ANGPTL8 are associated with various metabolic disorders and other health conditions. Elevated ANGPTL8 levels have been observed in individuals with type 2 diabetes mellitus (T2DM), obesity, and dyslipidemia. These associations suggest that ANGPTL8 may serve as a biomarker for these metabolic disturbances.
Research indicates ANGPTL8’s potential involvement in broader physiological and pathological processes. Studies have linked ANGPTL8 to inflammation, as it may dampen NF-κB activity, a pathway involved in inflammatory responses. ANGPTL8 has also been implicated in the progression of certain types of tumors, influencing tumor growth and metastasis.
ANGPTL8 is also being investigated for its potential role in circulatory system diseases. Its influence on triglyceride metabolism and lipid profiles suggests a connection to conditions like atherosclerosis, where elevated triglycerides contribute to plaque buildup in arteries. Further research aims to clarify whether ANGPTPL8 directly contributes to these health issues or if its altered levels are merely a reflection of the underlying disease state.
How ANGPTL8 Functions
ANGPTL8 primarily exerts its effects through interaction with ANGPTL3 and potentially ANGPTL4. For ANGPTL8 to effectively inhibit lipoprotein lipase (LPL), it forms a complex with ANGPTL3. This complex formation occurs intracellularly. Once secreted, the ANGPTL3-ANGPTL8 complex suppresses LPL activity in the bloodstream, influencing triglyceride breakdown and clearance.
The expression of ANGPTL8 is tightly regulated by physiological cues. Nutritional status plays a role, with ANGPTL8 levels decreasing during fasting and increasing after refeeding. Hormones such as insulin, as well as fatty acids, also regulate its expression. In humans, ANGPTL8 is predominantly expressed in the liver, with some presence in adipose tissue.