High-Fat Diet Promotes Macrophage-Mediated Hepatic Inflammation and Aggravates Diethylnitrosamine-Induced Hepatocarcinogenesis in Mice

Abstract

It has been reported that diet and nutrition play important roles in the occurrence and development of hepatocellular carcinoma (HCC). In this study, we investigated the potential tumor-promoting mechanisms of a high-fat diet (HFD) in mice with dietondiethylnitrosamine (DEN)-induced hepatocarcinogenesis. HFD significantly decreased the survival rate and induced severe liver dysfunction in DEN-induced mice, as indicated by increased serum glutamic-pyruvic transaminase (ALT), glutamic oxalacetic transaminase (AST), and alkaline phosphatase (ALP) levels and increased liver index, liver nodule count, and γ-glutamyltransferase (γ-GT) activity. Moreover, an increased number of fat droplets and HCCs were found in the livers of the HFD mice, who displayed little collagen in and around the liver cancer groove and the infiltration of large number of inflammatory cells, such as macrophages, compared with the control mice. HFD also significantly increased proliferating cell nuclear antigen (PCNA), nuclear factor-κB (NF-κB), cyclin D1, tumor necrosis factor (TNF), and interleukin-1 (IL-1) expression levels in the liver. In vitro , we found that the inducible nitric oxide synthase (iNOS) percentage increased in macrophages after palmitic acid treatment, as well as the secretion of inflammatory factors and cytokines such as interleukin-6(IL-6), interleukin-10(IL-10), CCL2, Interferon γ (IFN-γ), and TNF. Thus, our results demonstrate that an HFD may promote DEN-induced hepatocarcinogenesis in mice by destroying liver function and enhancing the inflammatory response by recruiting and polarizing macrophages in the liver. This study could therefore provide new insights into the tumor promoting effects of an HFD in HCC.

Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors

“…Wanten et al, 2002;Khan et al, 2018;Tam et al, 2020 ↑ adhesion, apoptosis, NLRP3, NO, IL-1β, IL-6, TNF-α, NF-κB, JNK, MKK4/7, IL-10, CCL2, IFN-γ M1 polarization, CD36; ↓ phagocytosis in macrophages. Calder et al, 1990a;de Lima et al, 2006;Kim et al, 2017;Lu et al, 2017;Wang et al, 2017Wang et al, , 2021Karasawa et al, 2018;Lancaster et al, 2018;Korbecki and Bajdak-Rusinek, 2019;Fu et al, 2020;Sano et al, 2020;Youk et al, 2021 Synthetic agonist GW9508 ↑ ROS, MMP-9, COX-2, IL-8, chemotaxis in neutrophils. Hidalgo et al, 2011;Manosalva et al, 2015;Mena et al, 2016;Souza et al, 2020 ↑ PLC, PLA2, AMPK, AA; ↓ IL-6 in macrophages.…”

“…High-fat diet (HFD) may promote hepatocarcinogenesis through an exacerbated inflammatory response that affects the liver function. In vivo experiments demonstrated that HFD affected liver function in mice, induced liver infiltration of macrophages, and increased expression of inflammatory factors, such as proliferating cell nuclear antigen (PCNA), NF-κB, cyclin D1, TNF-α, and IL-1β in the liver (Fu et al, 2020 ). In addition, to understand the link between obesity and inflammation, and its effects in pregnancy, Sano et al ( 2020 ) studied the in vivo and in vitro effects of palmitic acid in pregnant mice.…”

“…Also, palmitic acid induced M1 macrophage polarization and increased CD36 expression, a membrane glycoprotein that transports fatty acids, via decreased expression of the histone methyltransferase G9a (Lu et al, 2017 ; Wang et al, 2021 ). An in vitro assay demonstrated that palmitic acid induced the expression of iNOS and secretion of IL-6, IL-10, CCL2, IFN-γ, and TNF-α in mouse primary macrophages (Fu et al, 2020 ). Thus, the most recent studies have elucidated the role of palmitic acid not only in mediating the function of isolated macrophages but also the pro-inflammatory effects on macrophages in conditions such as obesity or when HFDs are ingested.…”

Lipid alterations in chronic liver disease and liver cancer

“… 16 Dysregulation of lipids plays important roles in both the development 17 and the progression 18 of liver cancer, which is a consequence of lipids being a vast and multifarious group of complex structured biomolecules. Lipids are involved in diverse biological processes in the body from energy storage 19 and metabolism, 20 to epigenetic regulation, 21 signal transduction, 22 immunoregulation, 23 inflammation, 24 and cell-cell recognition. 25 …”

The Role of the BH4 Cofactor in Nitric Oxide Synthase Activity and Cancer Progression: Two Sides of the Same Coin

“…Although the status of NOS expression was not showed, the results implicate altered NOS activity. On the other hand, different studies showed the pro-tumoral activity of NO-derived eNOS/iNOS in HCC growth [82,83]. González et al reported that sorafenib, a receptor tyrosine kinase, and MAPK pathway inhibitor, decreased eNOS activity and NO synthesis, attenuating proliferation and inducing apoptosis in HCC cell lines [83].…”