Development of Cilofexor, an Intestinally-Biased Farnesoid X Receptor Agonist, for the Treatment of Fatty Liver Disease.

The farnesoid X receptor (FXR) is a nuclear receptor that controls bile acid, lipid, and cholesterol metabolism. FXR-targeted drugs have shown promise in late-stage clinical trials for non-alcoholic steatohepatitis. Herein, we used clinical results from our first non-steroidal FXR agonist, 4-[2-[2-chloro-4-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methoxy]phenyl]cyclopropyl] benzoic acid (Px-102), to develop cilofexor, a potent, non-steroidal FXR agonist with a more manageable safety profile.

Inflammatory response of human coronary artery endothelial cells to saturated long-chain fatty acids.

Saturated long-chain fatty acids (SFAs) exert unfavourable metabolic effects (lipotoxicity) and induce apoptotic cell death (lipoapoptosis) in certain cell-types. Their contribution to inflammatory cell responses is unclear. We studied the expression of 113 inflammatory genes in human coronary artery endothelial cells (hCAECs) and their regulation by SFAs and unsaturated long-chain fatty acids (UFAs).

Protein kinase C iota mediates lipid-induced apoptosis of human coronary artery endothelial cells.

Apoptosis is involved in the development and progression of atherosclerotic lesions. Protein kinase C (PKC) signalling is of importance in atherosclerosis as well as apoptosis. Therefore, we tested the involvement of PKC in lipid-induced apoptosis of human coronary artery endothelial cells (HCAEC).

Hypomagnesemia and nephrocalcinosis in a patient with two heterozygous mutations in the CLDN16 gene.

We report the case of a 20-year-old male Caucasian patient with diagnosed nephrocalcinosis and a medical history of seizures and recurrent urinary tract infections. Laboratory investigations revealed clinical and biochemical abnormalities characteristic of familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Since FHHNC is caused by mutations in the CLDN16 gene encoding a renal tight junction protein, we sequenced the complete coding region of this gene and detected two heterozygous mutations, the known Leu151Phe (+453G-->T) mutation and a novel Cys120Arg (+358T-->C) mutation.