A Novel Mutation in LXRα Uncovers a Role for Cholesterol Sensing in Limiting Metabolic Dysfunction-Associated Steatohepatitis (MASH).

Liver x receptor alpha (LXRα, Nr1h3) functions as an important intracellular cholesterol sensor that regulates fat and cholesterol metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, MASH-like phenotypes can arise in the absence of large increases in triglycerides. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH suggesting that LXRα normally functions to impede the development of liver disease.

Measuring tryptophan dynamics using fast scan cyclic voltammetry at carbon fiber microelectrodes with improved sensitivity and selectivity.

Despite the fact that tryptophan (Trp) is an essential amino acid that humans typically obtain through diet, there are several interesting tryptophan dynamics at play in the body. Quantifying and understanding these dynamics are crucial in studies of depression, autism spectrum disorder, and other disorders that involve neurotransmitters directly synthesized from tryptophan. Here we detail the optimization of waveform parameters in fast scan cyclic voltammetry at carbon fiber microelectrodes to yield four-fold higher sensitivity and six-fold higher selectivity compared to previously reported methods. We demonstrate the utility of our method in measuring (1) exogenous Trp dynamics from administration of Trp to PC-12 cells with and without overexpression of tryptophan hydroxylase-2 and (2) endogenous Trp dynamics in pinealocyte cultures with and without stimulation via norepinephrine. We observed interesting differences in Trp dynamics in both model systems, which demonstrate that our method is indeed sensitive to Trp dynamics in different applications.

Liver X receptors and liver physiology.

The liver x receptors LXRα (NR1H3) and LXRß (NR1H2) are members of the nuclear hormone receptor superfamily of ligand dependent transcription factors that regulate transcription in response to the direct binding of cholesterol derivatives. Studies using genetic knockouts and synthetic ligands have defined the LXRs as important modulators of lipid homeostasis throughout the body. This review focuses on the control of cholesterol and fatty acid metabolism by LXRs in the liver and how modifying LXR activity can influence the pathology of liver diseases.

Role of Kalirin and mouse strain in retention of spatial memory training in an Alzheimer's disease model mouse line.

Nontransgenic and 3xTG transgenic mice, which express mutant transgenes encoding human amyloid precursor protein (hAPP) along with Alzheimer's disease-associated versions of hTau and a presenilin mutation, acquired the Barnes Maze escape task equivalently at 3-9 months of age. Although nontransgenics retested at 6 and 9 months acquired the escape task more quickly than naïve mice, 3xTG mice did not. Deficits in Kalirin, a multidomain protein scaffold and guanine nucleotide exchange factor that regulates dendritic spines, has been proposed as a contributor to the cognitive decline observed in Alzheimer's disease. To test whether deficits in Kalirin might amplify deficits in 3xTG mice, mice heterozygous/hemizygous for Kalirin and the 3xTG transgenes were generated. Mouse strain, age and sex affected cortical expression of key proteins. hAPP levels in 3xTG mice increased total APP levels at all ages. Kalirin expression showed strong sex-dependent expression in C57 but not B6129 mice. Decreasing Kalirin levels to half had no effect on Barnes Maze task acquisition or retraining in 3xTG hemizygous mice.