The Role of Vitamin K in Cholestatic Liver Disease

Abstract

Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.

The Nuclear Receptor PXR in Chronic Liver Disease

“…The liver is involved in the synthesis and transport of BAs [ 31 ], which are the result of cholesterol metabolism and act as emulsifiers to facilitate the absorption of liposoluble vitamins and lipids in the intestine, due to their amphiphilic nature [ 32 , 33 ]. A dysfunction of their synthesis in hepatocytes, an impairment or obstruction of bile flow or atypical bile secretion in proximity of cholangiocytes may induce cholestasis [ 32 ]. There are two main metabolic pathways for the synthesis of BAs, called either the classical (neutral) or alternative (acid) pathway [ 34 ].…”

“…The main outcome of the rate-limiting enzyme CYP7B1 is CDCA [ 34 ]. Once synthetized and before entering the bile canaliculi, the primary BAs are conjugated with glycine (in humans) and taurine (in humans and mice), released from hepatocytes, and stored in the gallbladder [ 32 ]. After meals, they are released into the small intestine to help the uptake of dietary lipids [ 39 ].…”

“…Once in the bowel, the gut microbiota is responsible for the deconjugation of primary BAs by the enzyme bile salt hydrolase (BSH) [ 34 ]. This reaction is followed by 7α-dehydroxylation and epimerization, leading the conversion of primary unconjugated into secondary conjugated BAs, such as lithocholic acid, deoxycholic acid, and ursodeoxycholic acid (UDCA) [ 31 , 32 ]. The 95% of BAs that are reabsorbed in the ileum by the enterohepatic cycle reach back to the liver [ 34 ].…”

“…The remaining 5% is not absorbed in the ileum but reaches the colon, where the gut microbiota perform their deamination and dehydroxylation, allowing their passive reabsorption through the colonic epithelium. The BAs that are not reabsorbed by colon cells are excreted by feces [ 32 , 39 ]. The complexity of these mechanisms, i.e., synthesis, conjugation, uptake, and export of BAs, explains the reason why their homeostasis needs to be finely regulated by several cellular pathways, including PXR-mediated signaling.…”

“…A role of PXR in BA homeostasis was reported for the first time by Staudinger and colleagues, who demonstrated that lithocholic acid and its metabolites could act as PXR activators [ 32 , 40 ]. Nevertheless, some controversial findings have been reported so far regarding the concentration of BAs able to trigger PXR-mediated signaling.…”