The Fibrinogen-like Domain of ANGPTL3 Facilitates Lipolysis in 3T3-L1 Cells by Activating the Intracellular Erk Pathway

Abstract

Background: ANGPTL3 stimulates lipolysis in adipocytes, but the underlying molecular mechanism is yet unknown. The C-terminal fibrinogen-like domain of ANGPTL3 (ANGPTL3-Fld) activates the AKT pathway in endothelial cells. Hence, we evaluated whether ANGPTL3-Fld stimulates lipolysis in adipocytes through the MAPK kinase pathway. Materials and Methods: 3T3-L1 adipocytes were treated with isoproterenol (ISO), ANGPTL3-Fld, or both. Lipolysis was evaluated through the release of free fatty acids (FFAs) in the culture medium. The activation status of intracellular kinases was evaluated with and without the inhibition of the BRAF–ERK arm of the MAPK pathway. Results: ANGPTL3-Fld alone was not able to activate lipolysis, while the combination of ANGPTL3-Fld and ISO determined a 10-fold enrichment of the FFA concentration in the culture medium with an incremental effect (twofold) when compared with ISO alone. ANGPTL3-Fld alone inhibited hormone-sensitive lipase (HSL), whereas the treatment with ISO induced the activation of HSL. The net balance of ANGPTL3-Fld and ISO cotreatment resulted in HSL activation. The results indicate that ANGPTL3-Fld generated an intracellular activation signal involving the MAPK–ERK pathway, possibly through the PDGFRβ—PLCγ-AMPK axis. Conclusion: ANGPTL3-Fld appears to act as a facilitator of lipolysis in adipocytes, and this effect was driven by a signal mediated by a pathway that is different from the canonical β-adrenergic stimulus.

Heterogeneity of non-alcoholic fatty liver disease (NAFLD): Implication for cardiovascular risk stratification

“…F. Baratta et al main causes of hepatic fat accumulation and central to the development of hyperlipidemia. Interestingly, this typical lipid profile might also depend on the reduced activity of lipoprotein lipase (LPL) due to an increased activity of ANGPTL3 and ANGPTL4, which represent the physiological circulating inhibitors of LPL [67][68][69]. Notably, plasma levels of ANGPTL3 and ANGPTL4 were found to be increased in obesity and T2DM as well as in NAFLD/NASH patients [70].…”

Membrane Protein Amuc_1100 Derived from Akkermansia muciniphila Facilitates Lipolysis and Browning via Activating the AC3/PKA/HSL Pathway

“…HSL, the major effector of lipolysis, is the downstream target of PKA ( Fig. 4E ) ( 22 , 23 ). Therefore, Western blotting was used to determine the effects of Amuc_1100 on the expression levels of different proteins and genes known to be related to lipolysis in vivo and in vitro ( Fig.…”

ANGPTL3 Deficiency and Risk of Hepatic Steatosis

“…8 Such an effect could be explained by enhanced lipoprotein lipase activity in oxidative tissues and possibly reduced adipose tissue lipolysis, resulting in a reduced flux of FFA into the liver. For example, we recently found that the fibrinogen-like domain of ANGPTL3 enhances lipolysis in cultured adipocytes derived from 3T3-L1 cells, 42 raising the possibility that FHBL2 may result in a decreased rate of in vivo adipose tissue lipolysis. It is possible that all of these mechanisms in concert might prevent an imbalance between the synthesis of triglycerides and apoB within hepatocytes, thereby preventing the development of excessive hepatic lipid accumulation.…”