Simple-type epithelial
keratins are
intermediate filament proteins important for mechanical stability and stress protection.
Keratin mutations predispose to human liver disorders, whereas their roles in
intestinal diseases are unclear. Absence of
keratin 8 (K8) in mice leads to
colitis, decreased Na/Cl uptake,
protein mistargeting, and longer crypts, suggesting that
keratins contribute to intestinal homeostasis. We describe the rate-limiting
enzyme of the ketogenic energy metabolism pathway, mitochondrial
3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), as a major down-regulated
protein in the K8-knockout (K8(-/-)) colon. K8 absence leads to decreased quantity and activity of HMGCS2, and the down-regulation is not dependent on the inflammatory state, since HMGCS2 is not decreased in
dextran sulfate sodium-induced
colitis.
Peroxisome proliferator-activated receptor α, a transcriptional activator of HMGCS2, is similarly down-regulated. Ketogenic conditions-
starvation or
ketogenic diet-increase K8(+/+) HMGCS2, whereas this response is blunted in the K8(-/-) colon. Microbiota-produced
short-chain fatty acids (SCFAs), substrates in the colonic
ketone body pathway, are increased in stool, which correlates with decreased levels of their main transporter, monocarboxylate transporter 1 (MCT1). Microbial populations, including the main SCFA-
butyrate producers in the colon, were not altered in the K8(-/-). In summary, the regulation of the SCFA-MCT1-HMGCS2 axis is disrupted in K8(-/-) colonocytes, suggesting a role for
keratins in colonocyte energy metabolism and homeostasis.