Augmented CPT1A Expression Is Associated with Proliferation and Colony Formation during Barrett’s Tumorigenesis

Abstract

Obesity is a known risk factor for the development of gastroesophageal reflux disease (GERD), Barrett’s Esophagus (BE) and the progression to esophageal adenocarcinoma. The mechanisms by which obesity contributes to GERD, BE and its progression are currently not well understood. Recently, changes in lipid metabolism especially in the context of a high fat diet have been linked to GERD and BE leading us to explore whether fatty acid oxidation plays a role in the disease progression from GERD to esophageal adenocarcinoma. To that end, we analyzed the expression of the rate-limiting enzyme, carnitine palmytoyltransferase 1A (CPT1A), in human tissues and cell lines representing different stages in the sequence from normal squamous esophagus to cancer. We determined uptake of palmitic acid, the most abundant fatty acid in human serum, with fluorescent dye-labeled lipids as well as functional consequences of stimulation with palmitic acid relevant to Barrett’s tumorigenesis, e.g., proliferation, characteristics of stemness and IL8 mediated inflammatory signaling. We further employed different mouse models including a genetic model of Barrett’s esophagus based on IL1β overexpression in the presence and absence of a high fat diet and deoxycholic acid to physiologically mimic gastrointestinal reflux in the mice. Together, our data demonstrate that CPT1A is upregulated in Barrett’s tumorigenesis and that experimental palmitic acid is delivered to mitochondria and associated with increased cell proliferation and stem cell marker expression.

piRNAs and miRNAs Can Bind to mRNA of <i>KLOTHO</i> and <i>FGF23</i> Genes

“…piR-6885965 also binds in this BSs cluster, but with a ΔG/ΔGm value of less than 90%, which is below the selection criterion for significant piR-NAs. The CPT1A gene is involved in fatty acid metabolism and manifests its effect during oncogenesis, diabetes, and cardiomyopathy [62][63][64][65][66][67]. Figure 4 shows the interaction schemes of piR-3215034 and piR-6885965 with mRNA of CPT1A gene, which show that their BSs are located in the same cluster from 99 nt to 137 nt.…”

Obesity, Dietary Fats, and Gastrointestinal Cancer Risk-Potential Mechanisms Relating to Lipid Metabolism and Inflammation

“…There is some evidence, albeit limited, that fatty acids may have distinct effects on gastrointestinal cancers. Palmitate upregulated carnitine palmitoyltransferase 1A (CPT1A) in the disease sequence from Barrett’s oesophagus to OAC, in both in vitro and mouse models, resulting in increased cell proliferation [ 186 ]. Importantly, CPT1A is a rate-limiting enzyme in FAO, whose substrate is palmitate, which has been linked with promoting cancer cell proliferation [ 187 ].…”

High-fat diet enhances cell proliferation and compromises intestinal permeability in a translational canine intestinal organoid model

“…Notably, PA has been associated with compromised gut insulin sensitivity [ 21 ] and gut barrier function [ 22 ]. Additionally, prolonged exposure to PA has been shown to hinder cell differentiation in different tissues [ 7 , 23 , 24 ].…”