Evidences for Expression and Location of ANGPTL8 in Human Adipose Tissue

Abstract

The metabolism of triglycerides (TGs) is regulated, among others, by the lipoprotein lipase (LPL) that hydrolyses the TGs on endothelial cells. In turn, LPL is inhibited by the ANGPTLs family of proteins, such as ANGPTL3, 4, and, 8; the latter is the least known. In this work, we have tried to establish the expression and localisation of the Angiopoietin-like 8 (ANGPTL8) protein in the visceral adipose tissue (VAT) of morbid-obese and non-obese patients. 109 subjects (66 women and 43 men) undergoing laparoscopic surgery participated in this study. A blood sample and a portion of the VAT were obtained, and the patients were classified according to their Body Mass Index (BMI) as non-obese (19.5–30 kg/m2) and morbid-obese (40–50 kg/m2). No significant changes in ANGPTL8 plasma levels were determined by EIA in obese patients. The immunocytochemistry and Western blotting showed the presence of increased ANGPTL8 in morbid-obese patients (p < 0.05). In-situ hybridisation and a real time polymerase chain reaction (RT-PCR) confirmed that the mRNA that encodes ANGPTL8 was present in adipocytes, without differences in their nutritional state (p = 0.89), and even in the endothelial cells. Our data suggests that ANGPT8 plasmatic levels do not change significantly in patients with morbid obesity, although there is a modest difference related to gender. Besides, we demonstrate that in visceral adipose tissue, ANGPTL8 is well defined in the cytoplasm of adipocytes coexisting with perilipin-1 and its mRNA, also is present in endothelial cells. These findings suggest the possibility that among other functions, ANGPTL8 could perform either a paracrine and/or an endocrine role in the adipose tissue.

Liver-specific knockdown of ANGPTL8 alters the structure of the gut microbiota in mice

“…ANGPTL8/betatrophin has shown its considerable association with diabetes and obesity as well as various metabolic biomarkers in glucose and lipid homeostasis (Wang et al 2016;Abu-Farha et al 2017). This hormone is reported to be highly enriched in human and mouse liver and adipose tissues (Chen et al 2019;von Loeffelholz et al 2017;Catalano-Iniesta et al 2020;Akimoto et al 2019;Mysore et al 2017). Previous studies focused on the roles of ANGPTL8 as a hormone that directly works on the endocrine system, while hardly any evidence showed that external mediators are involved in these processes (Siddiqa et al 2017;Wang et al 2016;Abu-Farha et al 2017;Wang et al 2017).…”

“…The angiogenin-like protein family includes eight members structurally similar to angiogenin and widely participate in the regulation of lipid metabolism, inflammation, haematopoietic stem cell activity and cancer cell invasion. ANGPTL8 is highly enriched in the human liver and various adipose tissues, whose levels were much lower in the other tissues, and recent studies suggested that ANGPTL8 showed similar tissue distribution in mice (Chen et al 2019;von Loeffelholz et al 2017;Catalano-Iniesta et al 2020;Akimoto et al 2019;Mysore et al 2017). ANGPTL8 has been reported to play a significant role in various metabolic diseases.…”

The Interplay between Angiopoietin-Like Proteins and Adipose Tissue: Another Piece of the Relationship between Adiposopathy and Cardiometabolic Diseases?

“…ANGPTL8 is mainly produced by the liver, but also by gut epithelium and adipose tissue [ 65 , 66 ]. While liver-derived ANGPTL8 is largely secreted in plasma, produced by adipocytes, remains intracellularly, particularly localized in nucleoplasm [ 67 , 68 , 69 ]. It is a small protein of 198 residues, capable of interaction with ANGPTL3, but exposing a coiled-coil domain only [ 7 , 70 ].…”

“…A specific transcription factor for ANGPTL8 is the carbohydrate-responsive element-binding protein (ChREBP), which is induced by insulin stimulation [ 91 ]. While hepatocyte-derived ANGPTL8 is mainly secreted, in WAT and BAT it remains in nucleoplasm [ 69 ]. According to this model, ANGPTL8 is secreted in complexes with ANGPTL3, thus inhibiting LPL in oxidative tissues and directing dietary TGs to adipose tissue for storage [ 7 , 70 ].…”

“…Morinaga et al using a self-developed and controlled ANGPTL8 assay found higher circulating levels of ANGPTL8, in T2DM patients, associated with increased levels of LDL-C, TGs, and reduced HDL-C [ 101 ]. Interestingly, differences in ANGPTL8 expression are observable in obese vs. non-obese patients: in obese patients, VAT shows increased levels of ANGPTL8 in the nucleoplasm, while serum levels remain similar to non-obese controls [ 69 ].…”