UC San Diego
Activation of Liver X Receptors in Kupffer Cells Modulates Inflammatory Transcriptional Programs During Liver Disease
- Author(s): Bruni, Cassi Molly
- Advisor(s): Glass, Christopher K
- et al.
Liver X Receptors (LXRs), composed of LXRα and LXRβ, are ligand activated nuclear receptors that are important regulators of cholesterol and lipid metabolism. LXRs control expression of genes involved in cholesterol efflux, fatty acid metabolism, and inflammation in tissues such as the liver and intestine. LXRα is highly expressed in liver resident macrophages, called Kupffer cells, which are involved in clearing pathogens from the portal circulation, as well as sensing tissue injury. During liver disease, such as nonalcoholic steatohepatitis (NASH), Kupffer cells are responsible for initiating a proinflammatory response program; therefore, I sought to understand the LXR-dependent responses modulating cholesterol accumulation and inflammation in Kupffer cells at both the steady state and during disease. I found a decreased expression of cholesterol efflux and inflammatory genes in Kupffer cells of mice lacking LXRs throughout all tissues but aimed to understand the function of LXRs intrinsic to Kupffer cells. Therefore, I studied a Lyz2 Cre and a novel Clec4f Kupffer cell specific Cre mouse lacking LXRs and saw an expansion of a new F4/80HiCd11bIntTim4Neg Kupffer cell population that is associated with fatty liver disease. Consequently, LXR activation may have beneficial properties, so pharmacological activation with a synthetic mimetic of the natural LXR ligand desmosterol was analyzed. Results suggest that this desmosterol mimetic dampens hepatic inflammation, lipid accumulation, and fibrosis, and may not only be targeting the liver, but also altering gene expression in the intestine as well. Thus, pharmacological activation of LXRs may act therapeutically in patients with fatty liver disease.