VALLIM Lab
During a normal day, our body undergoes many changes in metabolism, which requires rapid adaptation to different conditions. For example, after a meal, our cells transition from seeing minimal levels of nutrients such as glucose or lipids, to suddenly having a large influx of these metabolites.
These cells have to rapidly adapt to these large environmental changes to maximize their ability to take up, utilize, or store these metabolites for survival. Failure to adapt to these changes is linked to metabolic dysfunction, which can manifest as obesity, atherosclerosis, and liver disease.
We are interested in discovering novel molecular mechanisms that regulate adaptive metabolic processes using a combination of physiology, genetics, and biochemistry
Role of Transcriptional Factors in Regulating Lipid Metabolism
Rapid adaptation requires turning many genes on, a process that is regulated by transcription factors. Our lab has extensively studied a member of the nuclear receptor superfamily, called Farnesoid X Receptor (FXR). FXR is a ligand-activated transcription factor, meaning that it regulates genes when a ligand/nutrient, in this case a bile acid, binds to the receptor. Bile acids are multi-faceted lipids that can act both as signaling molecules and detergents that facilitate lipid absorption in the intestine.
FXR regulates gene programs that maintain bile acid homeostasis, but also control lipid metabolism, particularly triglyceride metabolism in the liver and intestine, as well as regulating hepato-protective and anti-inflammatory pathways.
We are also investigating novel transcription factors through untargeted transcriptomic analysis, in search of new mechanisms that control metabolism.
Metabolic Control via mRNA Decay
Just as metabolic adaptation requires gene programs to be activated and turned on, there are pathways that control turning genes off. We identified an RNA-binding protein (RBP) family (Zfp36 or Tis11) as gate-keepers of these so-called "off-switches". In the presence of a stimulus, these RBPs are rapidly activated, and they in turn target mRNAs in a sequence-dependent manner for degradation.
We have identified different conditions that regulate the expression of these RBPs, including FXR, and we are now working towards identifying pathways that are regulated at the level of mRNA stability. One pathway we have already identified is bile acid synthesis.
We have shown that FXR induces ZFP36L1 which then signals to degrade the rate-limiting enzyme of bile acid synthesis, CYP7A1. We are currently investigating how ZFP36 family members degrade targets using biochemical approaches, and what pathways they target using mouse physiology experiments coupled to big data analysis.
Physiological role of Bile Acids in Intestinal Lipid Absorption
We are interested in understanding how dietary lipids enter the body through intestinal absorption, in addition to the study of systemic lipid metabolism. Bile acids are crucial for the emulsification of dietary lipids in preparation for intestinal absorption. Since there are many types of bile acids, some with unknown function, we seek to understand how changing the bile acid pool affects dietary lipid absorption and downstream physiology.
We can disrupt various bile acid synthesis and metabolism genes using liver-directed CRISPR-Cas9 packaged in adeno-associated virus, which allows us to manipulate both the bile acid pool size and composition in adult animal models. Our lab has also optimized methods to measure intestinal lipid absorption, which include gas chromatography-mass spectrometry and oxygen bomb calorimetry. Using these tools coupled with extensive mouse physiology, we are seeking to understand how changes in bile acid levels and types affect metabolism and disease.