Hepatic JAK2 protects against atherosclerosis through circulating IGF-1
Tharini Sivasubramaniyam, … , Clinton S. Robbins, Minna Woo
Tharini Sivasubramaniyam, … , Clinton S. Robbins, Minna Woo
Published July 20, 2017
Citation Information: JCI Insight. 2017;2(14):e93735. https://doi.org/10.1172/jci.insight.93735.
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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 6

L-Jak2–/–ApoE–/– and L-Jak2–/–Ldlr–/– mice exhibit impaired hepatic growth hormone signaling.

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L-Jak2–/–ApoE–/– and L-Jak2–/–Ldlr–/– mice exhibit impaired hepatic gro...
L-Jak2–/–ApoE–/–, L-Jak2–/–Ldlr–/–, and littermate controls (L-Jak2+/+ApoE–/– or L-Jak2+/+Ldlr–/–, respectively) were fed an atherogenic diet containing either 0.2% cholesterol (for ApoE-null mice) or 1.25% cholesterol (for Ldlr-null mice) for 12 weeks, starting at 6 weeks of age. (A) Western blots and quantitative summary of JAK2, phospho-STAT5, total STAT5, phospho-STAT3, and total STAT3 in liver homogenates from L-Jak2–/–ApoE–/– mice (n = 5) and control L-Jak2+/+ApoE–/– mice (n = 5). Protein band intensity was quantified by ImageJ software, and levels of JAK2 were normalized to expression of GAPDH; levels of p-STAT5 and p-STAT3 were normalized first to expression of GAPDH and then normalized to expression of total STAT5 and STAT3, respectively. Values are presented as fold change over control group. (B) Quantitative PCR (qPCR) analysis of Igf1 mRNA expression in livers from L-Jak2–/–ApoE–/– mice (n = 7) and control L-Jak2+/+ApoE–/– mice (n = 6). Values are normalized to 18S mRNA levels and presented as fold change over control group. (C) Serum levels of IGF-1 measured in L-Jak2–/–ApoE–/– mice (n = 9) and control L-Jak2+/+ApoE–/– mice (n = 7). (D) Serum levels of IGF-1 measured in L-Jak2–/–Ldlr–/– mice (n = 9) and control L-Jak2+/+Ldlr–/– mice (n = 7). (E) Serum levels of growth hormone (GH) measured in L-Jak2–/–ApoE–/– mice (n = 15) and control L-Jak2+/+ApoE–/– mice (n = 12). (F) Serum levels of GH measured in L-Jak2–/–Ldlr–/– mice (n = 15) and control L-Jak2+/+Ldlr–/– mice (n = 11). In each of the panels, each dot in the scatter plot indicates an individual animal. Data represent mean ± SEM. Differences between groups were analyzed for statistical significance by Student unpaired t test. **P < 0.01, ***P < 0.001.