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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 1

Lipodystrophic mice are predisposed to hepatic metastasis.

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Lipodystrophic mice are predisposed to hepatic metastasis.
(A–D) Two-mon...
(A–D) Two-month-old FF and Con mice were injected with Bo1 cells via left ventricular chamber, and 12 days later tumor burden was analyzed. (A) In vivo BLI image; (B) ex vivo image of liver, bone, lung, and kidney; (C) gross appearance of Con and FF liver; and (D) quantification of tumor burden in liver, bone, lung, and kidney of Con and FF mice. n = 8–13. ROI, region of interest. (E–H) Two-month-old PPAR ADQ and Con mice were injected with Bo1 cells via left ventricular chamber, and 12 days later tumor burden was analyzed. (E) In vivo BLI image; (F) ex vivo image of liver, bone, lung, and kidney; (G) gross appearance of Con and FF liver 12 days after tumor injection; and (H) quantification of tumor burden in liver, bone, lung, and kidney of Con and FF mice. n = 7. Data are presented as mean ± SD. **P < 0.01, ***P < 0.001 as determined by unpaired 2-tailed t test.

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