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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 4

Tumor promotes lipolysis of steatotic liver.

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Tumor promotes lipolysis of steatotic liver.
(A) TG in control or FF liv...
(A) TG in control or FF liver explants cultured with or without Bo1 cells. n = 6. (B) Expression of ATGL and HSL in control or FF liver explants cultured with Bo1 cells. n = 4. (C) FFA in control or FF liver explants cultured with or without Bo1 cells. n = 6. (D) PET scan of 11C-palmitate uptake by control or FF liver 10 days after Bo1 intracardiac injection. (E) 11C-palmitate uptake quantification. n = 4. SUV, standardized uptake value. (F) FATP1 mRNA expression in cancer cells exposed to control or steatotic liver–conditioned medium. n = 3. Data are presented as mean ± SD. *P < 0.05, ***P < 0.001 as determined by unpaired 2-tailed t test (B, E, and F) or 2-way ANOVA test with analysis of variance with Holm-Šidák multiple-comparisons test (A and C).

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