Abstract
Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Angptl4 (angiopoietin-like 4), a primary target gene of the glucocorticoid receptor in hepatocytes and adipocytes, is required for hypertriglyceridemia and hepatic steatosis induced by the synthetic glucocorticoid dexamethasone. Angptl4 has also been shown to be required for dexamethasone-induced hepatic ceramide production. Here, we further examined the role of ceramide-mediated signaling in hepatic dyslipidemia caused by chronic glucocorticoid exposure. Using a stable isotope-labeling technique, we found that dexamethasone treatment induced the rate of hepatic de novo lipogenesis and triglyceride synthesis. These dexamethasone responses were compromised in Angptl4-null mice (Angptl4-/-). Treating mice with myriocin, an inhibitor of the rate-controlling enzyme of de novo ceramide synthesis, serine palmitoyltransferase long-chain base subunit 1 (SPTLC1)/SPTLC2, decreased dexamethasone-induced plasma and liver triglyceride levels in WT but not Angptl4-/- mice. We noted similar results in mice infected with adeno-associated virus-expressing small hairpin RNAs targeting Sptlc2. Protein phosphatase 2 phosphatase activator (PP2A) and protein kinase Cζ (PKCζ) are two known downstream effectors of ceramides. We found here that mice treated with an inhibitor of PKCζ, 2-acetyl-1,3-cyclopentanedione (ACPD), had lower levels of dexamethasone-induced triglyceride accumulation in plasma and liver. However, small hairpin RNA-mediated targeting of the catalytic PP2A subunit (Ppp2ca) had no effect on dexamethasone responses on plasma and liver triglyceride levels. Overall, our results indicate that chronic dexamethasone treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders.
Highlights
Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis
This proposed mechanism is in agreement with previous observations showing that glucocorticoid-induced hepatic steatosis and hypertriglyceridemia are dependent on the presence of Angptl4, a glucocorticoid receptor (GR) primary target gene [17]
This suggests that glucocorticoid effects on cell types other than hepatocytes are required for the enhancement of hepatic de novo lipogenesis (DNL) and TG synthesis
Summary
Chronic or excess glucocorticoid exposure causes lipid disorders such as hypertriglyceridemia and hepatic steatosis. Our results indicate that chronic dexamethasone treatment induces an ANGPTL4 – ceramide–PKC axis that activates hepatic de novo lipogenesis and triglyceride synthesis, resulting in lipid disorders. It has been proposed that the excess lipolysis induced by GC in white adipose tissue plays a role in the development of dyslipidemia and fatty liver [15, 16] This proposed mechanism is in agreement with previous observations showing that glucocorticoid-induced hepatic steatosis and hypertriglyceridemia are dependent on the presence of Angptl (angiopoietin-like 4), a GR primary target gene [17]. Angptl has been shown to be required for glucocorticoids to stimulate hepatic ceramide production, which activates protein phosphatase 2A and protein kinase C (PKC) to suppress insulin signaling in liver [19].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
