The Kemper lab has recently published two high-profile papers on metabolic regulation in the Journal of Clinical Investigation and Nature Communications.
The Kemper lab has recently published two high-profile papers on metabolic regulation: “Fasting-induced JMJD3 histone demethylase epigenetically activates mitochondrial fatty acid β-oxidation” in the Journal of Clinical Investigation and “Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis” in Nature Communications.
The Journal of Clinical Investigation paper was chosen as a journal highlight. The research provided novel insights into the role of JMJD3 in the hepatic response to fasting by showing that JMJD3 selectively regulates fatty acid, but not glucose, metabolism.
During fasting the liver engages two metabolic pathways to help the body (a) gluconeogenesis i.e. the production of glucose and (b) the breakdown of lipids via fatty acid oxidation. “Although both these processes are important during fasting, the first pathway becomes problematic in diabetic patients who already have trouble regulating the glucose levels in their blood, and fatty acid oxidation is also often defective contributing to excess weight gain in diabetics and fatty liver” said Jongsook Kim Kemper, Professor of Molecular and Integrative Physiology. “In such cases it is desirable to only increase fatty acid oxidation and not glucose production in the liver since glucose levels are already high.”
In this study, the Kemper lab discovered that JMJD3 is important for regulation of lipid breakdown but not glucose production in the liver. The protein plays a key role in increasing fatty acid oxidation by removing the methylation markers of specific histones, thereby increasing the expression of genes involved in fatty acid oxidation.
The study was originally started to understand the targets of SIRT1, a well-characterized deacetylase that mediates beneficial effects of calorie restriction and increases lifespan and health, said Kemper. “Since SIRT1 is also involved in both the hepatic responses to fasting, we examined proteins that interact with SIRT1 as a first step to determine whether SIRT1 regulates both glucose and lipid metabolism in the liver by the same mechanisms.
To their surprise, they discovered that JMJD3 not only interacts with SIRT1, but more importantly, selectively stimulates expression of SIRT1 target genes that are involved with fatty acid oxidation, while not affecting those involved in glucose production. “JMJD3 was discovered 10-15 years ago but a role for JMJD3 in metabolic regulation had not been demonstrated,” said Kemper. “In this study we have shown that JMJD3 is required for SIRT1-mediated beneficial effects including lipid lowering and insulin sensitization functions,” she said.
Understanding this pathway can help in developing therapeutic strategies for treating diabetic patients. An additional advantage of targeting JMJD3 is that it can lead to a decrease in the fat content of the liver, thereby counteracting fatty liver disorder in these patients.
The paper in Nature Communications reports studies on the response to feeding rather than fasting, the Kemper lab discovered a molecular signaling mechanisms by which bile acid levels are controlled by a negative feedback pathway between the gut and the liver. “Bile acids are synthesized from cholesterol and act as detergents, aiding the digestion of fat-soluble nutrients,” said Kemper. “It is also an important signaling molecule in metabolic regulation.” Due to its detergent properties, the levels of bile acids must be tightly controlled. An excess of bile acids can cause cellular damage, resulting in liver damage, intestinal disorders, and cancer, she said.
After a meal, bile in the gall bladder is secreted into the gut, and activates the intestinal FXR, a bile acid-sensing nuclear receptor, which is then targeted to the nucleus where it serves as a master regulator of genes that are involved in bile acid homeostasis, Kemper explained. “One such gene is FGF19, which encodes an intestinal hormone,” said Kemper. “FGF19 is then secreted from the gut and acts at the liver where it reduces bile synthesis.” In this process, the binding of FGF19 to the membrane of the liver cells initiates a signaling cascade which results in the addition of a phosphate group to the FXR present in the liver cells. This modification is necessary for FXR to enter into the nucleus, where FXR reduces the expression of genes involved in bile acid synthesis.
A key finding of the study is that this phosphorylation of FXR is mediated by the kinase, Src. Src is a well-known proto-oncogene i.e. a normal gene which can undergo mutations and thereby cause cancer, and Src is one of the primary targets of anti-cancer drugs, such as, Dasatinib, but a role for Src in metabolic regulation was not known. “In our studies, we showed that Src also plays a critical role in bile acid homeostasis by transmitting the FGF19 signal from the membrane to the nucleus, via phosphorylation of FXR, for inhibition of bile acid synthesizing genes” said Kemper. Thus, important new insights about the mechanisms of regulation of bile acid metabolism by FGF19 were revealed. Further, Dr. Kemper added that “inhibition of Src during cancer treatment leads to adverse effects such as liver toxicity and failure, so an interesting side result from our studies is that this toxicity may arise due to dysregulated bile acid levels.”
“These two studies emphasize that gene-selective and tissue-specific regulation of genes will be crucial for development of drugs for treating metabolic disorders and cancer that have minimal unwanted side effects,” said Kemper.
