Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells

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.

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“…In the fibrotic liver, KCs overexpressed platelet‐derived growth factor (PDGF), which was the main factor that activates HSCs [29]. In normal livers, most HSCs were in a quiescent condition, while in cirrhotic livers, HSCs were activated by soluble factors (such as PDGF), differentiated into myofibroblasts, and then produced excess ECM [30]. Cirrhosis‐induced SEC changes included a lack of capillarization, SEC fenestration, and the formation of organized basement membranes [31].…”

Identify Key Active Ingredients and Molecular Mechanisms of Jiangzhi Decoction on Non-alcoholic Fatty Liver Disease by Network Pharmacology Analysis

“…In general, PPAR activation is thought to be bene cial in NAFLD, and clinical trials of single/dual receptor agonists are underway [31]. Another important nuclear receptor LXRα acts as the negative regulator of cholesterol metabolism through the induction of hepatocyte cholesterol catabolism, excretion, and the reverse cholesterol transport pathway [35]. Furthermore, HNF4A/HNF4α (hepatocyte nuclear factor 4α; NR2A1) also belongs to the subfamily of nuclear receptors.…”

Identify Molecular Mechanisms of Jiangzhi Decoction on Nonalcoholic Fatty Liver Disease by Network Pharmacology Analysis and Experimental Validation

“…In general, PPAR activation is thought to be beneficial in NAFLD, and clinical trials of single/dual receptor agonists are underway [ 31 ]. Another important nuclear receptor LXR α acts as the negative regulator of cholesterol metabolism through the induction of hepatocyte cholesterol catabolism, excretion, and the reverse cholesterol transport pathway [ 35 ]. Furthermore, HNF4A/HNF4 α (hepatocyte nuclear factor 4 α ; NR2A1) also belongs to the subfamily of nuclear receptors.…”