The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease

“

TL;DR

This review summarizes the roles of nuclear receptors (NRs) in regulating hepatic cholesterol homeostasis and reverse cholesterol transport in nonalcoholic fatty liver disease (NAFLD). It highlights that cholesterol imbalance, rather than triglyceride accumulation, is a key driver of NAFLD progression, and NRs such as LXR, HNF4α, PPAR, FXR, and RXRα are critical in cholesterol synthesis, excretion, and storage. The clinical significance lies in identifying NRs as potential therapeutic targets for NAFLD and its associated extrahepatic diseases, though further research is needed to balance efficacy and adverse effects.

Full summary

3,200 CHARS

**Background:** Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease globally, affecting approximately 2 billion people, with a prevalence of 29.6% in China as of 2018. It ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). While initial theories focused on triglyceride accumulation, recent evidence emphasizes that cholesterol homeostasis imbalance is more critical. Nuclear receptors (NRs) are key transcriptional regulators of cholesterol metabolism, including synthesis, excretion, and storage, and play roles in reverse cholesterol transport (RCT). This review aims to summarize NR mechanisms in NAFLD pathogenesis and progression.

**Methods:** This is a narrative review of existing literature on NAFLD pathogenesis, focusing on NRs in hepatic cholesterol homeostasis and RCT. The authors synthesized findings from studies on NRs such as liver X receptor (LXR), hepatocyte nuclear factor 4 alpha (HNF4α), peroxisome proliferator-activated receptors (PPARs), Nur77, farnesoid X receptor (FXR), and retinoid X receptor alpha (RXRα). They also discussed drug research progress, including GFT505 (dual PPAR-α/δ agonist), MGL-3196 (THR-β agonist), SR9238 (LXR inverse agonist), and obeticholic acid (OCA, FXR agonist).

**Key Results:** The review details the roles of specific NRs: LXRα deficiency in mice leads to significant cholesterol accumulation in the liver when fed a high-cholesterol diet. LXR activation inhibits intestinal cholesterol absorption via NPC1L1 downregulation and promotes cholesterol efflux through ABCA1, ABCG1, and ABCG5/8. HNF4α knockout mice exhibit liver cholesterol accumulation, decreased serum total cholesterol, HDL cholesterol, and triglycerides, and increased serum bile acids. PPARα agonists (e.g., fenofibrate) increase fecal cholesterol excretion, and co-application with LXR agonists increases excretion >12-fold. Nur77 overexpression reduces hepatic triglyceride content and lowers SREBP1c expression; Csn-b treatment reduces liver lipid content by 39.9% in mice. FXR activation inhibits CYP7A1 via SHP and FGF19/FGFR4 pathways, and OCA therapy improves steatosis and hepatocellular ballooning in NAFLD patients, with pruritus as the most common adverse event. RXRα heterodimerizes with LXR, FXR, and PPAR to regulate cholesterol efflux and bile acid synthesis.

**Clinical Implications:** The dysregulation of NRs disrupts cholesterol homeostasis, contributing to NAFLD progression and associated atherosclerotic diseases. NRs are promising therapeutic targets: PPAR agonists (e.g., GFT505) improve insulin sensitivity and liver enzymes; THR-β agonists (e.g., MGL-3196) reduce hepatic fat; LXR inverse agonists (e.g., SR9238) inhibit steatosis and inflammation; and FXR agonists (e.g., OCA) improve NAFLD histology. However, challenges include adverse effects (e.g., LXR activation increases steatosis, OCA increases LDL and decreases HDL) and the need for tissue-specific or dual agonists. The review emphasizes the importance of NR cross talk (e.g., PPARγ-LXR cascade in RCT) and calls for further research to develop safe and effective therapies.