Dietary Fat Composition Affects Hepatic Angiogenesis and Lymphangiogenesis in Hepatitis C Virus Core Gene Transgenic Mice

Pan Diao; Yaping Wang; Fangping Jia; Xiaojing Wang; Xiao Hu; Takefumi Kimura; Yoshiko Sato; Kyoji Moriya; Kazuhiko Koike; Jun Nakayama; Naoki Tanaka

doi:10.1159/000525546

Dietary Fat Composition Affects Hepatic Angiogenesis and Lymphangiogenesis in Hepatitis C Virus Core Gene Transgenic Mice

Liver Cancer. 2022 Sep 16;12(1):57-71. doi: 10.1159/000525546. eCollection 2023 Feb.

Authors

Pan Diao¹, Yaping Wang^{1

2}, Fangping Jia^{1

3}, Xiaojing Wang^{1

4}, Xiao Hu^{1

5}, Takefumi Kimura⁶, Yoshiko Sato⁷, Kyoji Moriya⁸, Kazuhiko Koike⁹, Jun Nakayama⁷, Naoki Tanaka^{10

11

12}

Affiliations

¹ Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan.
² Department of Basic Nursing, Hebei Medical University, Shijiazhuang, China.
³ State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang Provincial Key Laboratory for Drug Clinical Research and Evaluation, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
⁴ Department of Gastroenterology, Lishui Hospital, Zhejiang University School of Medicine, Lishui, China.
⁵ Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China.
⁶ Department of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Japan.
⁷ Department of Molecular Pathology, Shinshu University School of Medicine, Matsumoto, Japan.
⁸ Department of Infection Control and Prevention, The University of Tokyo, Tokyo, Japan.
⁹ Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.
¹⁰ Department of Global Medical Research Promotion, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
¹¹ International Relations Office, Shinshu University School of Medicine, Matsumoto, Japan.
¹² Research Center for Social Systems, Shinshu University, Matsumoto, Japan.

Abstract

Introduction: Previous research has demonstrated that an isocaloric diet rich in trans-fatty acid (TFA), saturated fatty acid (SFA), and cholesterol (Chol) promoted steatosis-derived hepatic tumorigenesis in hepatitis C virus core gene transgenic (HCVcpTg) mice in different manners. Growth factor signaling and ensuing angiogenesis/lymphangiogenesis are key factors in hepatic tumorigenesis that have become recent therapeutic targets for hepatocellular carcinoma. However, the influence of dietary fat composition on these factors remains unclear. This study investigated whether the type of dietary fat would have a specific impact on hepatic angiogenesis/lymphangiogenesis in HCVcpTg mice.

Methods: Male HCVcpTg mice were treated with a control diet, an isocaloric diet containing 1.5% cholesterol (Chol diet), or a diet replacing soybean oil with hydrogenated coconut oil (SFA diet) for a period of 15 months or with shortening (TFA diet) for 5 months. The degree of angiogenesis/lymphangiogenesis and the expression of growth factors, including fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), were evaluated in non-tumorous liver tissues using quantitative mRNA measurement, immunoblot analysis, and immunohistochemistry.

Results: Long-term feeding of SFA and TFA diets to HCVcpTg mice increased the expressions of vascular endothelial cell indicators, such as CD31 and TEK receptor tyrosine kinase, in addition to lymphatic vessel endothelial hyaluronan receptor 1, indicating that angiogenesis/lymphangiogenesis were upregulated only by these fatty acid-enriched diets. This promoting effect correlated with elevated VEGF-C and FGF receptor 2 and 3 levels in the liver. c-Jun N-terminal kinase (JNK) and hypoxia-inducible factor (HIF) 1α, both key regulators of VEGF-C expression, were enhanced in the SFA- and TFA-rich diet groups as well. The Chol diet significantly increased the expressions of such growth factors as FGF2 and PDGF subunit B, without any detectable impact on angiogenesis/lymphangiogenesis.

Conclusion: This study revealed that diets rich in SFA and TFA, but not Chol, might stimulate hepatic angiogenesis/lymphangiogenesis mainly through the JNK-HIF1α-VEGF-C axis. Our observations indicate the importance of dietary fat species for preventing hepatic tumorigenesis.

Keywords: Angiogenesis; Growth factors; Hepatocellular carcinoma; Hypoxia-inducible factor; Lymphangiogenesis.

Grants and funding

The authors have declared no financial support.