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Hepatic lipids promote liver metastasis
Yongjia Li, … , Steven L. Teitelbaum, Wei Zou
Yongjia Li, … , Steven L. Teitelbaum, Wei Zou
Published September 3, 2020
Citation Information: JCI Insight. 2020;5(17):e136215. https://doi.org/10.1172/jci.insight.136215.
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Research Article Hepatology Oncology

Hepatic lipids promote liver metastasis

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Abstract

Obesity predisposes to cancer and a virtual universality of nonalcoholic fatty liver disease (NAFLD). However, the impact of hepatic steatosis on liver metastasis is enigmatic. We find that while control mice were relatively resistant to hepatic metastasis, those which were lipodystrophic or obese, with NAFLD, had a dramatic increase in breast cancer and melanoma liver metastases. NAFLD promotes liver metastasis by reciprocal activation initiated by tumor-induced triglyceride lipolysis in juxtaposed hepatocytes. The lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, where they are metabolized by mitochondrial oxidation to promote tumor growth. The histology of human liver metastasis indicated the same occurs in humans. Furthermore, comparison of isolates of normal and fatty liver established that steatotic lipids had enhanced tumor-stimulating capacity. Normalization of glucose metabolism by metformin did not reduce steatosis-induced metastasis, establishing the process is not mediated by the metabolic syndrome. Alternatively, eradication of NAFLD in lipodystrophic mice by adipose tissue transplantation reduced breast cancer metastasis to that of control mice, indicating the steatosis-induced predisposition is reversible.

Authors

Yongjia Li, Xinming Su, Nidhi Rohatgi, Yan Zhang, Jonathan R. Brestoff, Kooresh I. Shoghi, Yalin Xu, Clay F. Semenkovich, Charles A. Harris, Lindsay L. Peterson, Katherine N. Weilbaecher, Steven L. Teitelbaum, Wei Zou

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Figure 2

Obese mice are predisposed to hepatic metastasis.

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Obese mice are predisposed to hepatic metastasis.
(A and B) Two-month-ol...
(A and B) Two-month-old leptin–/– (ob/ob) and control mice were injected with Bo1 cells via left ventricular chamber, and 12 days later, tumor burden was analyzed. (A) Ex vivo image of liver, bone, lung, and kidney. (B) Quantification of tumor burden in liver, bone, lung, and kidney. n = 9–11. (C and D) WT mice were fed chow or HFD for 3 months, after which Bo1 cells were injected intracardiacally. (C) Ex vivo image of liver, bone, lung, and kidney and (D) quantification of tumor burden in liver, bone, lung, and kidney 12 days later. n = 8–13. (E and F) FF mice were injected intracardiacally with Bo1 cells 6 weeks after fat transplantation. (E) In vivo BLI image and (F) quantification of tumor burden in liver 12 days later. n = 8–9. (G) Following 2 months of metformin feeding, FF mice were injected with Bo1 cells. BLI quantification of liver tumor burden 12 days after injection. n = 4–5. Data are presented as mean ± SD. **P < 0.01, ***P < 0.001 as determined by unpaired 2-tailed t test (B and D) or 1-way ANOVA test with analysis of variance with Holm-Šidák multiple-comparisons test (F and G).

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