Contribution of palmitic acid-TLR4 axis in high fat diet-associated colorectal cancer cell proliferation

Epidemiology suggests that consumption of high fat diet (HFD) is associated with colorectal cancer growth. Understanding the molecular mechanisms that underlie the HFD-associated colorectal cancer growth will have a great implication. Our data clearly showed that HFD increased tumor size and tumor weight in xenograft models compared to matched control diet (CD). Interestingly, the growth of the tumors in the HFD- feeding models slowed down if HFD was replaced by CD, while tumors were getting bigger if HFD feeding persisted. Lipidomics studies showed that HFD increased palmitic acid and stearic acid levels in the tumors of the xenograft models. These 2 fatty acid levels in the tumors of the xenograft models were significantly reduced if HFD was replaced by CD. Furthermore, RNA sequencing showed that HFD upregulated toll like receptor 4 (TLR4) expressions in the tumors of the xenograft models, and the TLR4 expression levels were significantly reduced if HFD was replaced by CD. In addition, in CRC cell models, we found that only palmitic acid but not stearic acid upregulated TLR4 expressions. Palmitic acid also significantly increased CRC cell proliferation measured by CyQUANT® Cell Proliferation Assays. The palmitic acid-increased CRC cell proliferation was reduced in the presence of TLR4 inhibitors; these TLR4 inhibitors did not significantly affect the proliferation of control CRC cells.

Based on our preliminary data, we hypothesize that palmitic acid upregulates TLR4 expression in CRC, and the palmitic acid-TLR4 axis contributes to the HFD-associated CRC cell proliferation. We will set up different in vivo and in vitro models for this study. We will investigate the underlying mechanism of how palmitic acid upregulates TLR4 expression in CRC. Furthermore, we will study whether palmitic acid activates TLR4 in CRC cells. The contribution of the palmitic acid-TLR4 axis in HFD-associated CRC cell proliferation will also be investigated.

This study not only increases our understanding on the pathology of HFD-associated CRC, but also provides scientific rationale to suggest dietary intervention for the CRC patients.