Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2
Brandon C. Sos, Charles Harris, Sarah M. Nordstrom, Jennifer L. Tran, Mercedesz Balázs, Patrick Caplazi, Maria Febbraio, Milana A.B. Applegate, Kay-Uwe Wagner, Ethan J. Weiss
Brandon C. Sos, Charles Harris, Sarah M. Nordstrom, Jennifer L. Tran, Mercedesz Balázs, Patrick Caplazi, Maria Febbraio, Milana A.B. Applegate, Kay-Uwe Wagner, Ethan J. Weiss
View: Text | PDF | Corrigendum
Research Article Metabolism

Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2

Abstract

Non-alcoholic fatty liver disease is associated with multiple comorbid conditions, including diabetes, obesity, infection, and malnutrition. Mice with hepatocyte-specific disruption of growth hormone (GH) signaling develop fatty liver (FL), although the precise mechanism underlying this finding remains unknown. Because GH signals through JAK2, we developed mice bearing hepatocyte-specific deletion of JAK2 (referred to herein as JAK2L mice). These mice were lean, but displayed markedly elevated levels of GH, liver triglycerides (TGs), and plasma FFAs. Because GH is known to promote lipolysis, we crossed GH-deficient little mice to JAK2L mice, and this rescued the FL phenotype. Expression of the fatty acid transporter CD36 was dramatically increased in livers of JAK2L mice, as was expression of Pparg. Since GH signaling represses PPARγ expression and Cd36 is a known transcriptional target of PPARγ, we treated JAK2L mice with the PPARγ-specific antagonist GW9662. This resulted in reduced expression of liver Cd36 and decreased liver TG content. These results provide a mechanism for the FL observed in mice with liver-specific disruption in GH signaling and suggest that the development of FL depends on both GH-dependent increases in plasma FFA and increased hepatic uptake of FFA, likely mediated by increased expression of CD36.

Authors

Brandon C. Sos, Charles Harris, Sarah M. Nordstrom, Jennifer L. Tran, Mercedesz Balázs, Patrick Caplazi, Maria Febbraio, Milana A.B. Applegate, Kay-Uwe Wagner, Ethan J. Weiss

×

Figure 6

Expression of FAT (Cd36) is significantly increased in livers of JAK2L mice and augments uptake of plasma FFA, leading to FL.

Options: View larger image (or click on image) Download as PowerPoint
Expression of FAT (Cd36) is significantly increased in livers of JAK2L m...
Normalized expression of Cd36 (A) and Slc27a genes (B) in livers of male and female JAK2L and control adult mice. Values are derived from Affymetrix Mouse Gene 1.0 ST arrays and are normalized to male control levels (n = 5 for each group). (C) CD36 and actin Western blots. Individual liver samples (n = 3) were incubated with antibodies against CD36 (upper blot) and actin (lower blot). The first lane is molecular weight standards (upper blot, 62 kDa; lower blot, 49 and 38 kDa). Lanes 2 and 3 (labeled CD36) are heart tissue from wild-type and CD36-knockout mice. Lanes 4–6 and 7–9 are liver samples from control and JAK2L mice, respectively. The arrowhead points to the CD36 band. (D) Quantified density (intensity × mm2 [int × mm2]) of the CD36 bands from the liver blot in C. (E) Normalized expression of Pparg and Cd36 from livers from each of 4 groups from the JAK2L-little intercross (n = 3–4 for each group). Values are derived from real-time quantitative PCR experiments and are normalized to male control levels. Specific comparisons are indicated. (F) Normalized expression of Cd36 from livers of male control and JAK2L mice after a 2-week treatment with the PPARγ-specific antagonist GW9662 (G) (4 mg/g) or vehicle (V) (n = 5 for each group). (G) Quantity of TG in liver extracts from the mice in F. All values are expressed as mean ± SEM. †P = 0.015, **P < 0.01, ***P < 0.001.