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. 2019 Aug 8;5(17):e131310.
doi: 10.1172/jci.insight.131310.

Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma

Kevin C Corbit  1 , Camella G Wilson  1 , Dylan Lowe  1 , Jennifer L Tran  1 , Nicholas B Vera  2 , Michelle Clasquin  2 , Aras N Mattis  3 , Ethan J Weiss  1
Affiliations

Adipocyte JAK2 mediates spontaneous metabolic liver disease and hepatocellular carcinoma

Kevin C Corbit et al. JCI Insight. .

Abstract

Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are liver manifestations of the metabolic syndrome and can progress to hepatocellular carcinoma (HCC). Loss of Growth Hormone (GH) signaling is reported to predispose to NAFLD and NASH through direct actions on the liver. Here, we report that aged mice lacking hepatocyte Jak2 (JAK2L), an obligate transducer of Growth Hormone (GH) signaling, spontaneously develop the full spectrum of phenotypes found in patients with metabolic liver disease, beginning with insulin resistance and lipodystrophy and manifesting as NAFLD, NASH and even HCC, independent of dietary intervention. Remarkably, insulin resistance, metabolic liver disease, and carcinogenesis are prevented in JAK2L mice via concomitant deletion of adipocyte Jak2 (JAK2LA). Further, we demonstrate that GH increases hepatic lipid burden but does so indirectly via signaling through adipocyte JAK2. Collectively, these data establish adipocytes as the mediator of GH-induced metabolic liver disease and carcinogenesis. In addition, we report a new spontaneous model of NAFLD, NASH, and HCC that recapitulates the natural sequelae of human insulin resistance-associated disease progression. The work presented here suggests a attention be paid towards inhibition of adipocyte GH signaling as a therapeutic target of metabolic liver disease.

Keywords: Hepatology; Insulin; Liver cancer; Metabolism; Mouse models.

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Conflict of interest statement

Conflict of interest: NBV and MC are employees and shareholders of Pfizer Inc.

Figures

Figure 1
Figure 1. Hepatic GH resistance does not correlate with IR in mice lacking adipocyte Jak2.
Serum (A) IGF1 and (B) GH levels in 16-hour-fasted CON, JAK2L, and JAK2LA mice. (C) Blood glucose and (D) serum insulin levels in ad lib–fed (shown in black) and mice fasted 16 hours (shown in red). (E) Homeostatic assessment model of insulin resistance (HOMA-IR) values. (F) ITT in CON (black), JAK2L (red), and JAK2LA (green) mice. n = 9–13 (A, B, D, and E), 10–15 (C), and 6–8 (F). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way (A, B, and E) and 2-way ANOVA (C, D, and F).
Figure 2
Figure 2. JAK2L mice are lipodystrophic and have a defective fasted-to-fed response in adipose tissue.
(A) Body weight in grams (g) of ad lib–fed and 16-hour-fasted control CON, JAK2L, and JAK2LA mice. (B) Percentage of body weight lost following a 16-hour fast. (C) Percentages of lean and fast mass. Amount of (D) epididymal and (E) inguinal fat mass as a percentage of total body weight. (F) H&E staining of inguinal fat pads from 16-hour-fasted mice (original magnification, ×10). (G) Inguinal adipose levels (n = 3 per condition) of phosphorylated (T389) p70S6K (top) and total p70S6K (bottom) in 16-hour-fasted (–) or 30-minute-refed (+) mice as determined by Western blot. (H) Densitometric quantification of Western blots from (G) plotting phosphorylated T389/total p70S6K. n = 10–15 (A and B), 12–17 (C), and 5–7 (D and E). *P < 0.05; **P < 0.01; ****P < 0.0001 by 1-way (B and E) or 2-way (A, C, and H) ANOVA.
Figure 3
Figure 3. Loss of hepatocyte Jak2 promotes liver damage and dyslipidemia in an adipocyte Jak2–dependent manner.
(A) Liver weight as a percentage of total body weight in 16-hour-fasted CON, JAK2L, and JAK2LA mice. Hepatic (B) triglycerides and (C) total cholesterol levels in 16-hour-fasted mice. (D) Alanine aminotransferase (ALT), (E) aspartate aminotransferase (AST), (F) alkaline phosphatase (AP), (G) nonesterified fatty acids (NEFAs), (H) triglycerides, (I) cholesterol, (J) high-density lipoprotein (HDL), and (K) low-density lipoprotein (LDL) levels in 16-hour-fasted serum. n = 5–7 (A), 9–12 (B and C), and 9–13 (D–K). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 1-way ANOVA.
Figure 4
Figure 4. Loss of hepatocyte Jak2 promotes NAFLD and NASH in an adipocyte Jak2–dependent manner.
(A) H&E and (B) trichrome staining of liver sections from CON, JAK2L, and JAK2LA mice. (C) Percentages of hepatosteatosis, (D) ballooning, and (E) inflammatory loci observed in liver sections. (F) Fibrosis staging score. (G) Brunt staging score. n = 10–12. ***P < 0.001; ****P < 0.0001 by 1-way ANOVA.
Figure 5
Figure 5. Loss of hepatocyte Jak2 promotes HCC in an adipocyte Jak2–dependent manner.
(A) Pictures of gross livers from CON (left), JAK2L (middle), and JAK2LA mice (right). (B) Liver nodules on a JAK2L liver. (C) H&E and trichrome staining of liver sections from control mice (left) and JAK2L nodules (right). Scale bar: 1 mm. (D) Immunohistochemistry of sections from JAK2L liver nodules stained with anti–glutamine synthetase (top), anti-glypican-3 (middle), and CK19 (bottom). Scale bar: 900 um. (E) Contingency evaluation of HCC incidence showing the number of mice with HCC-negative (HCC –ve) and -positive (HCC +ve) tumors, n = 17–24. P value determined by χ2 testing.
Figure 6
Figure 6. GH treatment induces hepatic lipid deposition via adipocyte Jak2.
Lipidomics heatmaps of individual hepatic (A) triacylglycerol (TAG), (B) diacylglycerol (DAG), (E) cholesterol ester (CE), and (F) ceramide (CER) species in vehicle-treated (Veh-treated) or GH-treated CON and JAK2A mice. Total hepatic (C) TAG, (D) DAG, (G) CE, and (H) CER levels. *P < 0.05; **P < 0.01 by 2-way ANOVA. For lipidomics heatmaps, all values of individual lipid species are expressed as the log2 ratio to Veh-treated CON mice and visualized by the log2 scale to the right of the heatmap. n = 4–5.
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