Nuclear receptors and nonalcoholic fatty liver disease

Abstract

Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

Keywords: CAR; FXR; LXR; NAFLD; NASH; PCBs; PPAR; PXR; TAFLD; TASH.

Fig. 1

PPAR in NAFLD. The peroxisome proliferator activated receptors (PPAR) are activated by free fatty acids, specific eicosanoids, and dietary xenobiotics. The principle role of hepatic PPARα is to upregulate lipid oxidation in the fasting state, while inducing fibroblast growth factor 21 (FGF21). In the fed state, PPARβ/δ promotes lipid uptake and oxidation in skeletal muscle; while PPARγ promotes lipid uptake and storage in adipose tissue, while inducing adiponectin expression. The blue highlight around the liver, muscle and adipose is indicative of the tissues in which PPARα, PPARβ/δ, and PPARγ are highly expressed.

Fig. 2

PXR in NAFLD. The pregnane X receptor (PXR) is activated in the intestine by dietary intake of exogenous ligands and commensal bacterial production of indoles and other activating compounds. The principle role of PXR in the intestine is to maintain barrier function and reduce inflammation, as well as to regulate intestinal transcription of metabolic enzymes. Hepatic PXR activation regulates phase I–III xenobiotic detoxification as well as modulating glucose and fatty acid metabolism. The weight of evidence indicates that PXR activation worsens obesity, steatosis, and insulin resistance while decreasing hepatic inflammation and fibrosis, even though PXR is not expressed in adipose tissue. The blue highlight around the liver, intestine, gall bladder, and pancreas is indicative of the tissues PXR is highly expressed in.

Fig. 3

CAR in NAFLD. The constitutive androstane receptor (CAR) is activated by dietary xenobiotics in the post-prandial state. The principle role of CAR activation is to upregulate detoxification pathways in the liver to protect the organism against toxic ingestions or dietary metabolites. More recently, CAR activation has also been shown to impact NAFLD as well as energy metabolism in the liver, pancreas, and adipose tissue. CAR activation decreased hepatic steatosis and inflammation while decreasing obesity and diabetes. CAR is highly expressed in the liver (blue highlight).

Fig. 4

LXR in NAFLD. Increased cholesterol in the post-prandial state is sensed by the brain which synthesizes oxysterols to provide feedback via liver X receptor (LXR) activation to up-regulate reverse cholesterol transport and inhibit inflammation to attenuate systemic cholesterol toxicity. In rodents but not humans, hepatic LXR activation increases bile acid synthesis as a compensatory mechanism for handling the liver’s increased cholesterol load. Hepatic LXR activation also facilitates fatty acid synthesis from dietary nutrients (via increased SREBP-C and FAS) and decreases hepatic FGF-21 production. In this way, excess dietary nutrients may be stored as fat. LXR is highly expressed in the liver (blue highlight).

Fig. 5

FXR in NAFLD. The farnesoid X receptor (FXR) is activated in the intestine by bile acids released from gallbladder in response to post-prandial event. The principle role of FXR in the intestine is to upregulate FGF-19, which travels via portal circulation to the liver where it binds FGFR4 to inhibit CYP7A1 activation and subsequently bile acid synthesis. Intestinal FXR activation leads to efflux of bile acids to circulation and elimination by renal excretion. Hepatic FXR activation plays a critical role in cholesterol, fatty acid, and glucose metabolism, inflammation and fibrosis, insulin resistance and carcinogenesis in NAFLD. Hepatic FXR activation also upregulates FGF-21 expression that acts as autocrine, paracrine and endocrine factors to regulate adipose browning and hepatic lipid and glucose metabolism. The blue highlight around the liver, intestine, gall bladder, and pancreas demonstrates tissues with high FXR expression.