It has long been recognized that liver activity changes after eating. New research has found that the same nuclear receptors that modulate the production and secretion of glucagon, autophagy, and bile acids play important clinical roles in cholestasis and hyper coagulation.
“Networks of nuclear receptors integrate metabolism throughout the body,” explained David Moore, PhD, Professor of Molecular and Human Genetics and Molecular and Cell Biology, Baylor College of Medicine, Dallas, TX. “In the liver, FXR and PPARα are reciprocal moderators of bile acids, fatty acids and other pathways. They are involved in whole body metabolic integration.”
Dr. Moore presented the latest findings on “Nuclear Receptors Coordinate Liver Energy Balance” during the Friday morning plenary session. Much of the work he described was performed using genetic knockout mice, but applications in the human genome have direct clinical application.
One of the most widely recognized functions of FXR is the regulation of bile acid homeostasis. FXR also plays a key role in the regulation of autophagy. Long considered little more than a mechanism to recycle amino acids or an emergency nutrient pathway, autophagy also serves important adaptive and protective roles.
Autophagy enhances the availability of nutrients, allows the selective degradation of defective proteins and organelles, maintains intracellular quality control, enhances innate and adaptive immunity and suppresses aging and tumorgenesis. The process is regulated by nutrients, controlled largely by the nutrient sensing nuclear receptors FXR and PPARα.
In the fed state, FXR decreases bile acid synthesis as it increases the synthesis of proteins and glycogen. In the fasting state, PPARα enhances peroxisome proliferation, fatty acid oxidation, and production of fibroblast growth factor 21.
The two receptors exhibit similar coordinated activity to regulate autophagy, Dr. Moore explained. FXR and PPARα compete for binding sites on all 231 autophagy genes but have opposing transcriptional output to regulate autophagy.
These animal model findings have been used at Baylor Miraca Genetics Laboratory to unravel puzzling cases of progressing familial intrahepatic cholestasis. Three genes are known to play roles in this rare genetic condition. PFIC1 affects phospholipid transport, PFIC2 is a bile acid transporter, and PFIC3 is a phosphatidylcholine flippase. The Baylor lab performed whole exome sequencing on four neonates from two different families with familiar intrahepatic cholestasis and found a loss of FXR function in all four.
Two of the patients had liver transplants at 22 and four months and were healthy at their last visit. The other two died while waiting for new livers.
All four had the expected elevated bile acids, Dr. Moore said. They also had severe coagulopathy. Prothrombin time and INR values were two to four times higher than normal. Both Factor V and Factor Vii were suppressed and none of the children responded to vitamin K. “What do bile acids have to do with coagulation?” Dr. Moore asked. “It turns out that FXR directly regulates coagulation. One of the effects of elevated bile acids is to increase coagulation.”
FXR also targets three fibrinogen genes, albumin and transferrin. It turns out that FXR is a key regulator for the entire liver secretome. And protein synthesis and secretion is one of the important functions of the liver.
A healthy adult liver synthesizes about 25 grams of protein daily, Dr. Moore said. For basic researchers, 25 grams is a single lab mouse. For clinicians and patients, 25 grams is four eggs, about half of the recommended daily allowance of protein. Protein synthesis requires about eight percent of the total energy production of the liver.
“FXR activation is a license to secrete,” Dr. Moore said. “Secretion is nutrient intensive and nutrient expensive. FXR malfunction can cause loss of liver function and severe coagulopathy, making this a very relevant clinical finding.”