Abstract
Although high-fat diet (HFD) has been implicated in the development of colorectal cancer (CRC), the critical signaling molecule that mediates the cancer growth is not well-defined. Identifying the master regulator that controls CRC growth under HFD can facilitate the development of effective therapeutics for the cancer treatment. In this study, the global lipidomics and RNA sequencing data show that, in the tumor tissues of CRC-bearing mouse models, HFD not only increases tumor weight, but also the palmitic acid level and TLR4 expression, which are reduced when HFD is replaced by control diet. These concomitant changes suggest the roles of palmitic acid and TLR4 in CRC growth. Subsequent studies show that palmitic acid regulates TLR4 expression in PU.1-dependent manner. Knockdown of PU.1 or mutations of PU.1-binding site on TLR4 promoter abolish the palmitic acid-increased TLR4 expression. The role of palmitic acid/PU.1/TLR4 axis in CRC growth is further examined in cell model and animal models that are fed either HFD or palmitic acid-rich diet. More importantly, iTRAQ proteomics data show that knockdown of TLR4 changes the metabolic enzyme profiles in the tumor tissues, which completely abolish the HFD-enhanced ATP production and cancer growth. Our data clearly demonstrate that TLR4 is a master regulator for CRC growth under HFD by programming cancer metabolism.
Highlights
Studies demonstrate that inflammation, changes in gut microbiota and release of adipokines under obesity conditions are the players that regulate colorectal cancer (CRC) growth [1,2,3]
To better identify the molecular mechanisms that Toll-like receptor 4 (TLR4) expression regulate the CRC growth under high-fat diet (HFD) feeding, we randomly Since palmitic acid increased TLR4 mRNA levels, we investigated selected half of the mice in the HD group to have matched whether the acid affected TLR4 gene transcription
Our data clearly demonstrate that HFD feeding increases palmitic acid levels in CRC, which in turn increases TLR4 expressions by increasing PU.1 level and PU.1-dependent TLR4 gene transcription
Summary
Changes in gut microbiota and release of adipokines under obesity conditions are the players that regulate colorectal cancer (CRC) growth [1,2,3]. The activation of TLR4 by long-chain saturated fatty acid seems to be exclusive for palmitic acid. The palmitic acid-activated TLR4 regulates the proinflammatory signaling pathways [8, 9], and underlies the development of insulin resistance and leptin resistance in metabolic disorders [10]. A study shows that palmitic acid, by activating TLR4/MyD88 signaling pathway, recruits proinflammatory monocytes and macrophages to the islets and induces β-cell dysfunction in obese mouse models [10]. Another study shows that in the hypothalamus of the dietinduced obesity mouse model, activation of TLR4 by palmitic acid elicits inflammatory responses that result in the functional resistance to leptin [11]. Whether palmitic acid affects TLR4 expression is not known
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