Effects of Angiopoietin-Like 3 on Triglyceride Regulation, Glucose Homeostasis, and Diabetes

Abstract

Angiopoietin-like 3 (ANGPTL3) is a regulator of plasma triglyceride (TRG) levels due to its inhibitory action on the activity of lipoprotein lipase (LPL). ANGPTL3 is proteolytically cleaved by proprotein convertases to generate an active N-terminal domain, which forms a complex with ANGPTL8 orchestrating LPL inhibition. ANGPTL3-4-8 mouse model studies indicate that these three ANGPTL family members play a significant role in partitioning the circulating TRG to specific tissues according to nutritional states. Recent data indicate a positive correlation of ANGPTL3 with plasma glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in insulin-resistant states. The aim of this review is to critically present the metabolic effects of ANGPTL3, focusing on the possible mechanisms involved in the dysregulation of carbohydrate homeostasis by this protein. Heterozygous and homozygous carriers of ANGPTL3 loss-of-function mutations have reduced risk for type 2 diabetes mellitus. Suggested mechanisms for the implication of ANGPTL3 in carbohydrate metabolism include the (i) increment of free fatty acids (FFAs) owing to the enhancement of lipolysis in adipose tissue, which can induce peripheral as well as hepatic insulin resistance; (ii) promotion of FFA flux to white adipose tissue during feeding, leading to the attenuation of de novo lipogenesis and decreased glucose uptake and insulin sensitivity; (iii) induction of hypothalamic LPL activity in mice, which is highly expressed throughout the brain and is associated with enhanced brain lipid sensing, reduction of food intake, and inhibition of glucose production (however, the effects of ANGPTL3 on hypothalamic LPL in humans need more clarification); and (iv) upregulation of ANGPTL4 expression (owing to the plasma FFA increase), which possibly enhances insulin resistance due to the selective inhibition of LPL in white adipose tissue leading to ectopic lipid accumulation and insulin resistance. Future trials will reveal if ANGPTL3 inhibition could be considered an alternative therapeutic target for dyslipidemia and dysglycemia.

Relationship between hepatic and systemic angiopoietin‐like 3, hepatic Vitamin D receptor expression and NAFLD in obesity

“…This mechanism, which is increased in obesity, may lead to increased peripheral and liver insulin resistance 36 and intrahepatic fat accumulation. Moreover, ANGPTL3 up‐regulates ANGPTL4 expression by increasing FFA flux 37 ; this evidence is in line with our finding of a positive correlation between hepatic ANGPTL3 and ANGPTL4 expression.…”

Serum angiopoietin-like 3 levels are elevated in obese non diabetic men but are unaffected during an oral glucose tolerance test

“…Thus, the present study suggests that serum ANGPTL3 levels do not seem to be involved in short-term regulation of carbohydrate metabolism. However, previous studies have shown that ANGPTL3 levels are abnormally increased in insulin-resistant state and obesity, with worsening glucose metabolism and enhancing lipolysis in adipose tissues 19 , 37 . This could indicate the possible role of ANGPTL3 in regulating glucose metabolism at long-term, which could progressively lead to type 2 diabetes and other metabolic lifelong diseases 19 , 37 .…”

Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab

“…Further, ANGPTL-8 is also believed to play a role in fatty acid metabolism. Just like the other angiopoietin-like proteins, ANGPTL-8 is highly regulated and is most active in the prandial state, which then increases the ANGPTL-8 and -3 pathway [ 45 , 46 , 47 ]. However, studies have shown that in mice models, concentrations of ANGPTL-8 affect triglyceride levels in a linear fashion [ 48 ].…”