Circulating hepatokine ANGPTL8, but not ANGPTL3, is increased in low-capacity runner (LCR) rats

Metabolic syndrome, including hypertension, hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and visceral adiposity, increases your risk of heart disease, stroke, and type 2 diabetes. Unfortunately, there is an increase in prevalence of metabolic syndrome among women. While lifestyle interventions (e.g., diet and exercise), are desirable for preventing morbidity and mortality, the genetic predisposition of some people to these conditions means that therapeutic interventions are also necessary. Hepatokines are liver-derived hormones which convey energy status and assist in controlling the availability of endogenous nutrients to a variety of peripheral tissues. Hepatokines, therefore, are important signaling molecules that allow the liver to communicate with other organs throughout the body. Angiopoietin-like Protein (ANGPTL3) is a secreted glycoprotein and hepatokine. ANGPTL3 directly inhibits lipoprotein lipase, an enzyme responsible for hydrolyzing circulating triglycerides. Therefore, it promotes an increase in circulating triglyceride levels without altering phospholipid secretion or uptake. Moreover, ANGPTL3 inhibition has been unequivocally associated with reduced hypercholesterolemia and atherosclerosis. Therefore, we hypothesized that circulating ANGPTL3 expression would be increased in low-capacity runner (LCR) rats. LCR is an animal model metabolic syndrome and presents vascular dysfunction. On the other hand, rats selectively bred for high intrinsic capacity (HCR), presents a healthy state and reduced inflammatory markers. Plasma was extracted from the blood of female LCR (28-week-old), as well as HCR, and control [high-response trainer (HRT)]. Western blot for ANGPTL3 expression was performed. Opposite our hypothesis, we did not observe any difference in circulating ANGPTL3 in LCR relative to HCR (arbitrary units, LCR: 7.5±1.1 vs. HCR: 7.2±0.9, p>0.05) or HRT (arbitrary units, LCR: 7.5±1.1 vs. HRT: 8.2±1.5, p>0.05). However, it has been established that ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase. Therefore, we performed another Western blot for ANGPTL8 expression. We observed that ANGPTL8 is significantly increased in LCR relative to HCR (arbitrary units, LCR: 12.2±0.6 vs. HCR: 9.7±1.1, p<0.05) and HRT (arbitrary units, LCR: 12.2±0.6 vs. HRT: 9.2±0.4, p<0.05). Overall, these data suggest that the hepatokine ANGPTL8 may be a more physiologically relevant target for the treatment of metabolic syndrome associated with low-intrinsic exercise capacity. NHLBI (R00HL151889), NIGMS (1P20GM103641 - Pilot Project), UofSC SOM (Startup funds). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.