Abstract
Excess dietary cholesterol intake and the dysregulation of cholesterol metabolism are associated with the pathogenesis and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and fibrosis. Hepatic accumulation of free cholesterol induces activation of nonparenchymal cells, including Kupffer cells, macrophages, and hepatic stellate cells, which leads to persistent inflammation and fibrosis. The nuclear receptors liver X receptor α (LXRα) and LXRβ act as negative regulators of cholesterol metabolism through the induction of hepatocyte cholesterol catabolism, excretion, and the reverse cholesterol transport pathway. Additionally, LXRs exert an anti-inflammatory effect in immune cell types, such as macrophages. LXR activation suppresses acute hepatic inflammation that is mediated by Kupffer cells/macrophages. Acute liver injury, diet-induced steatohepatitis, and fibrosis are exacerbated by significant hepatic cholesterol accumulation and inflammation in LXR-deficient mice. Therefore, LXRs regulate hepatic lipid metabolism and immunity and they are potential therapeutic targets in the treatment of hepatic inflammation that is associated with cholesterol accumulation.
Highlights
The liver plays an essential role in the metabolism of nutrients, such as proteins, lipids and carbohydrates, and xenobiotics
The nuclear receptors liver X receptor α (LXRα; called NR1H3) and LXRβ (NR1H2) are transcription factors that regulate the expression of key genes that are involved in lipid and cholesterol metabolism [3]
LXRs are expressed in hepatic nonparenchymal cells, including leukocytes, hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs), and they regulate immunity and inflammation, contributing to counter-regulation of hepatic inflammation, diet-induced nonalcoholic steatohepatitis (NASH), and fibrosis
Summary
The liver plays an essential role in the metabolism of nutrients, such as proteins, lipids and carbohydrates, and xenobiotics. The nuclear receptors liver X receptor α (LXRα; called NR1H3) and LXRβ (NR1H2) are transcription factors that regulate the expression of key genes that are involved in lipid and cholesterol metabolism [3]. LXRs belong to the NR1H nuclear receptor subfamily along with the bile acid receptor farnesoid X receptor (NR1H4) and they are closely related to the NR1I subfamily, which contains vitamin D receptor (NR1I1), pregnane X receptor (NR1I2), and constitutive androstane receptor (NR1I3) These NR1H and NR1I subfamily receptors regulate bile acid metabolism by sensing the metabolic environment [4]. The liver plays important roles in both lipid metabolism and innate immunity as a gateway for dietary signals, and LXRs are suggested to have a gatekeeper function in the liver. Function-selective LXR agonists might have promising therapeutic potential for liver diseases by regulating lipid metabolism and immune responses. We review the role of LXRs in hepatic nonparenchymal cell function and the pathogenesis of liver diseases
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call