Background In nephrotic syndrome, damage to the podocytes of the kidney produces severe hypercholesterolemia for which novel treatments are urgently needed. Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an important regulator of plasma cholesterol levels and therapeutic target. Here, we tested the role of PCSK9 in mediating the hypercholesterolemia of nephrotic syndrome. Methods and Results Both nephrotoxic serum (NTS) treatment, which induces immune-mediated damage of the podocyte, and genetic ablation of the podocyte produced hypercholesterolemia and a 7- to 24-fold induction in plasma PCSK9 in mice. Conversely, patients with nephrotic syndrome showed a decrease in plasma cholesterol and plasma PCSK9 upon remission of their disease (p<0.05, n=47-50). The induction of plasma PCSK9 in nephrotic syndrome appeared to be due to increased secretion of PCSK9 from the hepatocyte coupled with decreased clearance. Interestingly, knockout of Pcsk9 ameliorated the effects of NTS on plasma lipids. Thus, in the presence of NTS, mice lacking hepatic Pcsk9 showed a 40% to 50% decrease in plasma cholesterol and triglycerides. Moreover, the ability of NTS treatment to increase the proportion of LDL-associated cholesterol (from 9% in vehicle-treated Flox mice to 47% after NTS treatment), was lost in mice with hepatic deletion of Pcsk9 (5% in both the presence and absence of NTS). Conclusions Podocyte damage triggers marked inductions in plasma PCSK9, and knockout of Pcsk9 ameliorates dyslipidemia in a mouse model of nephrotic syndrome. These data suggest that PCSK9 inhibitors may be beneficial in patients with nephrotic syndrome-associated hypercholesterolemia.
Background: Evidence suggests that fibroblast growth factor 21 (FGF21) inhibits longitudinal bone growth. Results: FGF21 antagonizes the growth hormone (GH) stimulatory effects on thymidine incorporation and collagen X expression in chondrocytes. Conclusion: FGF21 inhibits bone growth by antagonizing GH effects on chondrocyte proliferation and differentiation. Significance: Increased FGF21 during food restriction may contribute to growth failure by directly inhibiting chondrogenesis.
Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of low-density lipoprotein (LDL) cholesterol and cardiovascular disease (CVD) risk, and is an emerging therapeutic target. Objective We compared serum PCSK9 levels in young adults, with and without type 2 diabetes. Subjects and Methods Cross-sectional analysis was conducted in a cohort, aged 15 to 26 years, in Cincinnati, OH, from 2005 to 2010. Serum PCSK9 levels were measured in 94 youth with type 2 diabetes, 93 obese control subjects, and 99 lean control subjects. Correlative analyses were conducted to determine significant covariates of PCSK9 by group and sex, and multivariate linear regression models were used to study the independent determinants of PCSK9. Results In females, PCSK9 levels were significantly increased in the obese and type 2 diabetes subjects relative to the lean controls (P < 0.01). Moreover, PCSK9 was positively correlated with multiple metabolic parameters in females: body mass index (BMI), systolic blood pressure (SBP), fasting glucose, fasting insulin, and C-reactive protein (CRP) levels (P≤0.02). In males, PCSK9 levels were decreased overall compared to females (P=0.03), and did not differ between the lean, obese, or type 2 diabetes groups. Conclusions Obesity and type 2 diabetes were associated with significantly higher levels of PCSK9 in young women, but not in young men. These data suggest that sex could modify the effects of obesity and diabetes on PCSK9 in young adults.
Background: The risk of cardiovascular disease in type 1 diabetes remains extremely high, despite marked advances in blood glucose control and even the widespread use of cholesterol synthesis inhibitors. Thus, a deeper understanding of insulin regulation of cholesterol metabolism, and its disruption in type 1 diabetes, could reveal better treatment strategies. Methods: To define the mechanisms by which insulin controls plasma cholesterol levels, we knocked down the insulin receptor, FoxO1, and the key bile acid synthesis enzyme, CYP8B1. We measured bile acid composition, cholesterol absorption, and plasma cholesterol. In parallel, we measured markers of cholesterol absorption and synthesis in humans with type 1 diabetes treated with ezetimibe and statins in a double-blind crossover study. Results: Mice with hepatic deletion of the insulin receptor showed marked increases in 12α-hydroxylated bile acids (12HBAs), cholesterol absorption, and plasma cholesterol. This phenotype was entirely reversed by hepatic deletion of FoxO1 . FoxO1 is inhibited by insulin, and required for the production of 12HBAs, which promote intestinal cholesterol absorption and suppress hepatic cholesterol synthesis. Knockdown of Cyp8b1 normalized 12HBA levels and completely prevented hypercholesterolemia in mice with hepatic deletion of the insulin receptor (n=5-30) as well as mouse models of type 1 diabetes (n=5-22). In parallel, the cholesterol absorption inhibitor, ezetimibe, normalized cholesterol absorption and LDL-cholesterol in patients with type 1 diabetes as well as, or better than, the cholesterol synthesis inhibitor, simvastatin (n=20). Conclusions: Insulin, by inhibiting FoxO1 in the liver, reduces 12HBAs, cholesterol absorption, and plasma cholesterol levels. Thus, type 1 diabetes leads to a unique set of derangements in cholesterol metabolism, with increased absorption rather than synthesis. These derangements are reversed by ezetimibe, but not statins, which are currently the first line of lipid-lowering treatment in type 1 diabetes. Taken together, these data suggest that a personalized approach to lipid lowering in type 1 diabetes may be more effective and highlight the need for further studies specifically in this group of patients.
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