Cellular Metabolism and Dose Reveal Carnitine-Dependent and -Independent Mechanisms of Butyrate Oxidation in Colorectal Cancer Cells

Abstract

Dietary fiber has been suggested to suppress colorectal cancer development, although the mechanisms contributing to this beneficial effect remain elusive. Butyrate, a fermentation product of fiber, has been shown to have anti-proliferative and pro-apoptotic effects on colorectal cancer cells. The metabolic fate of butyrate in the cell is important in determining whether, it acts as an HDAC inhibitor or is consumed as a short-chain fatty acid. Non-cancerous colonocytes utilize butyrate as the primary energy source whereas cancerous colonocytes increase glucose utilization through the Warburg effect. In this study, we show that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. We demonstrate that colorectal cancer cells utilize both a carnitine-dependent and carnitine-independent mechanism that contributes to butyrate oxidation. The carnitine-dependent mechanism is contingent on butyrate concentration. Knockdown of CPT1A in colorectal cancer cells abolishes butyrate oxidation. In terms of selectivity, the carnitine-dependent mechanism only regulated butyrate oxidation, as acetate and propionate oxidation were carnitine-independent. Carnitine decreased the action of butyrate as an HDAC inhibitor and suppressed induction of H3 acetylation by butyrate in colorectal cancer cells. Thus, diminished oxidation of butyrate is associated with decreased HDAC inhibition and histone acetylation. In relation to the mechanism, we find that dichloroacetate, which decreases phosphorylation of pyruvate dehydrogenase, increased butyrate oxidation and that this effect was carnitine-dependent. In conclusion, these data suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells. J. Cell. Physiol. 231: 1804-1813, 2016. © 2015 Wiley Periodicals, Inc.

Oral administration of propionic acid during lactation enhances the colonic barrier function

“…The major mechanisms involves the direct inhibition of histone deacetylases (HDACs) to directly regulate gene expression [28–30] and signaling through G-protein-coupled receptors (GPCRs) [31–33]. Propionic acid was the most potent and efficacious ligand for GPCR4 [34].…”

Short Chain Fatty Acids in the Colon and Peripheral Tissues: A Focus on Butyrate, Colon Cancer, Obesity and Insulin Resistance

“…In contrast, SCFAs are present in the colonic lumen at a range of 50–100 mM [ 95 ] and the CPT system appears to have a more prominent role in butyrate uptake at higher concentrations. Mechanistic analysis of the Warburg effect in HCT116 colorectal cancer cells identified decreased intracellular carnitine levels relative to noncancerous fetal human colonocytes [ 96 ]; additionally, Western blotting revealed decreased expression of organic cation/carnitine transporter 2 (OCTN2), a sodium-coupled cotransporter for carnitine, in the HCT116 cell line [ 96 ]. A similar experiment illustrated that undifferentiated Caucasian colon adenocarcinoma (Caco)-2 cancer cells exhibited negligible expression of OCTN2, whereas their mature Caco-2 counterparts (which more closely resemble small intestinal enterocytes) expressed OCTN2 at the brush border membrane [ 97 ].…”

“…Moreover, hypermethylation of the solute carrier family 5 member 8 ( Slc5a8 ) gene, which codes for a sodium-dependent butyrate transporter, has been observed in both cancerous colonocytes as well as aberrant crypt foci [ 98 ]. These data suggest that impairment of butyrate uptake and metabolism characterizes early neoplasia in the colon and could potentially contribute to cancer progression [ 92 , 96 , 97 , 98 ]. To this end, multiple lines of research have suggested that a combination treatment of butyrate and carnitine/acetylcarnitine can exert greater effects on cancerous cells than butyrate treatment alone, possibly by enhancing butyrate localization to the mitochondria [ 99 , 100 ].…”

Possible Prophylaxes of Aloe Vera Gel Ingestion to Butyrate Metabolism

“…Han A. group showed that butyrate oxidation is decreased in cancerous colonocytes compared to non-cancerous colonocytes. The data obtained suggest that colorectal cancer cells decrease butyrate oxidation through inhibition of pyruvate dehydrogenase, which is carnitine-dependent, and provide insight into why butyrate shows selective effects toward colorectal cancer cells [32] . Rutkowski M. and his group showed that the microbiome does not act in isolation; a patient's genetic background can also greatly influence response to therapy.…”