Rationale: Glucagon is a key hormone that regulates the adaptive metabolic responses to fasting. In addition to maintaining glucose homeostasis, glucagon participates in the regulation of cholesterol metabolism, however, the molecular pathways underlying this effect are incompletely understood. Objective: We sought to determine the role of hepatic glucagon receptor (Gcgr) signaling in plasma cholesterol regulation and identify its underlying molecular mechanisms. Methods and Results: We show that Gcgr signaling plays an essential role in low-density lipoprotein (LDL) cholesterol homeostasis through regulating the proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. Silencing of hepatic Gcgr or inhibition of glucagon action increased hepatic and plasma PCSK9 and resulted in lower LDL receptor protein and increased plasma LDL-cholesterol. Conversely, treatment of WT mice with glucagon lowered LDL-cholesterol levels, whereas this response was abrogated in Pcsk9−/− and Ldlr−/− mice. Our gain- and loss-of-function studies identified exchange protein activated by cAMP-2 (Epac2) and Ras-related protein-1 (Rap1) as the downstream mediators of glucagon’s action on PCSK9 homeostasis. Moreover, mechanistic studies revealed that glucagon affected the half-life of PCSK9 protein without changing the level of its mRNA, indicating that Gcgr signaling regulates PCSK9 degradation. Conclusions: These findings provide novel insights into the molecular interplay between hepatic glucagon signaling and lipid metabolism and describe a new post-transcriptional mechanism of PCSK9 regulation.
Purpose of review: The purpose of this review is to highlight the recent findings of one of the most promising therapeutic targets in low-density lipoprotein (LDL) cholesterol management, proprotein convertase subtilisin/kexin type 9 (PCSK9). Recent findings: Endoplasmic reticulum (ER) cargo receptor, surfeit locus protein 4 (SURF4) interacts with PCSK9 and regulates its exit from ER and its secretion. Once secreted, PCSK9 binds to heparin sulfate proteoglycans on the hepatocyte surface and this binding is required for PCSK9-LDL receptor (LDLR) complex formation and LDLR degradation. Post-transcriptionally, recent work has shown that PCSK9 gets degraded in the lysosomes by activation of the glucagon receptor signaling, providing more data on the hormonal regulation of PCSK9. Finally, human studies with PCSK9 inhibitors offered more evidence on their benefits and safe use. Summary: Recent work on the regulation of PCSK9 has enhanced our understanding of its biology, which may provide important information for future PCSK9-based therapies.
Background: Non-alcoholic fatty liver disease (NAFLD) is currently the major cause of chronic liver disease globally. Bile acids (BAs) have emerged as relevant signaling molecules that are associated with NAFLD development. This study was aimed to examine the association of serum total bile acids (TBAs) with NAFLD in a large population of Chinese subjects. Methods: This cross sectional study recruited 152,336 participants from the Second Xiangya Hospital, China. NAFLD was diagnosed based on the presence of hepatic steatosis on ultrasonography, without significant alcohol consumption and other known causes for chronic liver disease. A multivariate logistic regression model was used to test for the association of serum TBAs with NAFLD, adjusting for conventional risk factors of NAFLD. Results: A total of 27.4% of the participants had NAFLD. Patients with NAFLD had slightly higher TBA levels than those without, 3.4 vs. 3.0 μmol/L (p < 0.001). However, TBA levels were not associated with NAFLD in the multivariate logistic regression model, which adjusted for age, gender and other acknowledged risk factors for NAFLD (OR = 1.00. 95% CI: 1.00-1.00, p = 0.797). Conclusions: We found that the serum TBA levels were not associated with NAFLD. Future studies in a large population, focusing on serum BA composition may improve the understating of the role of BAs in NAFLD.
Leukocytoclastic vasculitis is a rare form of immune-mediated vasculitis that might be caused by infections or autoimmune diseases or might be precipitated by specific medications. We describe a 65-year-old patient, who was receiving vancomycin for a methicillin-sensitive Staphylococcus aureus permacath infection. Vancomycin was chosen due to medication non-adherence and the patient’s desire to receive antimicrobial therapy in conjunction with his scheduled dialysis sessions. The patient’s medical history was notable for untreated hepatitis C infection and end-stage renal disease, requiring hemodialysis three times a week. Vancomycin was administered during dialysis sessions. After one week of therapy, the patient developed bilateral lower extremity purpura. Skin biopsy was suggestive of leukocytoclastic vasculitis with an absence of intravascular thrombi. Serum cryoglobulins were negative, making cryoglobulinemia due to HCV infection unlikely. Following cessation of vancomycin therapy, the rash gradually disappeared with scarring in the form of post-purpuric hyperpigmentation. Despite its widespread use, vancomycin is a rare cause of leukocytoclastic vasculitis. Clinicians should keep in mind a wide range of differential diagnosis of bilateral lower extremity purpura as treatment differs depending on its underlying etiology.
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