Hepatic JAK2 protects against atherosclerosis through circulating IGF-1
Tharini Sivasubramaniyam, Stephanie A. Schroer, Angela Li, Cynthia T. Luk, Sally Yu Shi, Rickvinder Besla, David W. Dodington, Adam H. Metherel, Alex P. Kitson, Jara J. Brunt, Joshua Lopes, Kay-Uwe Wagner, Richard P. Bazinet, Michelle P. Bendeck, Clinton S. Robbins, Minna Woo
Tharini Sivasubramaniyam, Stephanie A. Schroer, Angela Li, Cynthia T. Luk, Sally Yu Shi, Rickvinder Besla, David W. Dodington, Adam H. Metherel, Alex P. Kitson, Jara J. Brunt, Joshua Lopes, Kay-Uwe Wagner, Richard P. Bazinet, Michelle P. Bendeck, Clinton S. Robbins, Minna Woo
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Research Article Metabolism Vascular biology

Hepatic JAK2 protects against atherosclerosis through circulating IGF-1

Abstract

Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content. JAK2’s essential role in growth hormone signalling in liver that resulted in reduced IGF-1 with hepatic Jak2 deficiency played a causal role in exacerbating atherosclerosis. As such, restoring IGF-1 either pharmacologically or genetically attenuated atherosclerotic burden. Together, our data show hepatic Jak2 to play a protective role in atherogenesis through actions mediated by circulating IGF-1 and, to our knowledge, provide a novel liver-centric mechanism in atheroprotection.

Authors

Tharini Sivasubramaniyam, Stephanie A. Schroer, Angela Li, Cynthia T. Luk, Sally Yu Shi, Rickvinder Besla, David W. Dodington, Adam H. Metherel, Alex P. Kitson, Jara J. Brunt, Joshua Lopes, Kay-Uwe Wagner, Richard P. Bazinet, Michelle P. Bendeck, Clinton S. Robbins, Minna Woo

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Figure 5

L-Jak2–/–Ldlr–/– mice develop profound hepatic steatosis but do not display glucose intolerance, insulin resistance, or systemic inflammation.

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L-Jak2–/–Ldlr–/– mice develop profound hepatic steatosis but do not dis...
L-Jak2–/–Ldlr–/– mice and L-Jak2+/+Ldlr–/– littermate controls were fed an atherogenic diet containing 1.25% cholesterol for 12 weeks, starting at 6 weeks of age. (A) Representative images of H&E and oil red O (ORO) staining of liver sections from L-Jak2–/–Ldlr–/– mice (n = 9 and 5) and control L-Jak2+/+Ldlr–/– mice (n = 6 and 4). Scale bars: 300 μm (black), 50 μm (white). (B) Total hepatic triglyceride (TG) content in L-Jak2–/–Ldlr–/– mice (n = 5) and control L-Jak2+/+Ldlr–/– mice (n = 6). Results are normalized to tissue weight. (C) Liver weight normalized to total body weight in L-Jak2–/–Ldlr–/– mice (n = 5) and control L-Jak2+/+Ldlr–/– mice (n = 6). (D) Random blood glucose from L-Jak2–/–Ldlr–/– mice (n = 14) and control L-Jak2+/+Ldlr–/– mice (n = 10). (E) Glucose tolerance test in overnight-fasted L-Jak2–/–Ldlr–/– mice (n = 15) and control L-Jak2+/+Ldlr–/– mice (n = 11). Mice received glucose (1 g/kg) i.p., and blood glucose was measured sequentially for 120 minutes. (F) Insulin tolerance test in 4 hour–fasted L-Jak2–/–Ldlr–/– mice (n = 16) and control L-Jak2+/+Ldlr–/– mice (n = 11). Mice received insulin (0.75 units/kg) i.p., and blood glucose was measured sequentially for 60 minutes. Data are expressed as a percentage of basal (fasting) glucose. (G) Fasting serum insulin levels from L-Jak2–/–Ldlr–/– mice (n = 6) and control L-Jak2+/+Ldlr–/– mice (n = 7). (H) Serum levels of TNFα, IL-6, and MCP-1 in L-Jak2–/–Ldlr–/– mice (n = 4–5) and control L-Jak2+/+Ldlr–/– mice (n = 3–6). MCP-1, monocyte chemoattractant protein-1. (I) Total number of leukocytes in blood from L-Jak2–/–Ldlr–/– mice (n = 7) and control L-Jak2+/+Ldlr–/– mice (n = 5). (J and K) Frequency and absolute numbers of Ly6Chi monocytes in red cell–lysed blood from L-Jak2–/–Ldlr–/– mice (n = 7) and control L-Jak2+/+Ldlr–/– mice (n = 5) using flow cytometry. Ly6Chi monocytes were defined based on CD115+Ly6ChiLy6G– expression. Total serum (L) cholesterol; P = 0.1061 and (M) triglycerides from L-Jak2–/–Ldlr–/– mice (n = 7) and control L-Jak2+/+Ldlr–/– mice (n = 4). (N–Q) Distribution of serum cholesterol among lipoprotein fractions determined by fast performance liquid chromatography (FPLC) and total serum VLDL, LDL, and HDL cholesterol were quantified from FPLC serum lipoprotein profiles from L-Jak2–/–Ldlr–/– mice (n = 7) and control L-Jak2+/+Ldlr–/– mice (n = 4). Each dot in scatter plots indicate an individual animal. Data represent mean ± SEM. Differences between groups were analyzed for statistical significance by Student unpaired t test. *P < 0.05, **P < 0.01, ***P < 0.001.