Review Article | Published:

Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR

Nature Reviews Molecular Cell Biology volume 13, pages 213224 (2012) | Download Citation

Abstract

Nuclear receptors are integrators of hormonal and nutritional signals, mediating changes to metabolic pathways within the body. Given that modulation of lipid and glucose metabolism has been linked to diseases including type 2 diabetes, obesity and atherosclerosis, a greater understanding of pathways that regulate metabolism in physiology and disease is crucial. The liver X receptors (LXRs) and the farnesoid X receptors (FXRs) are activated by oxysterols and bile acids, respectively. Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism.

Key points

  • Nuclear receptors have an integral role in cellular processes, translating metabolic, hormonal and nutritional signals to changes in gene expression.

  • Liver X receptor (LXR) and farnesoid X receptor (FXR) form a heterodimer with retinoid X receptor (RXR) and mediate changes in gene expression following activation by their natural ligands, oxysterols and bile acids, respectively.

  • LXRs regulate whole-body cholesterol homeostasis by controlling the uptake, transport and excretion of cholesterol in a tissue-selective manner.

  • In addition to having effects on cholesterol regulation, LXR activation has been shown to mediate changes in lipid and carbohydrate metabolism in the liver and in extra-hepatic tissues such as adipose, skeletal muscle and the pancreas.

  • FXR is a central regulator of bile acid homeostasis, controlling key steps in the production and enterohepatic circulation of bile acids.

  • FXR mediates its effects on bile acid metabolism via direct induction of target genes and by indirect repression via induction of small heterodimer partner (SHP).

  • Recent studies have demonstrated an additional role for FXR in the regulation of lipid and glucose metabolism.

  • Alterations to the above-mentioned pathways are associated with obesity, diabetes and atherosclerosis. LXR and FXR act on mulitple pathways involved in these metabolic diseases, making these nuclear receptors attractive targets for pharmaceutical intervention on multiple levels.

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Acknowledgements

This work was supported by US National Institutes of Health (NIH) grants HL066088 and HL030568.

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  1. Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, 675 Charles E Young Drive South, Los Angeles, California 90095, USA.

    • Anna C. Calkin
    •  & Peter Tontonoz

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Glossary

High-density lipoprotein

(HDL). Lipoprotein that transports cholesterol from the periphery to the liver; known as 'good' cholesterol.

Very low-density lipoprotein

(VLDL). Lipoprotein that enables fats and cholesterol to move in the bloodstream. It is the primary carrier of hepatic triglyceride to the periphery. It is composed of triglycerides, apolipoproteins and cholesterol. VLDL is formed in the liver and transported to the periphery; known as 'very bad' cholesterol.

Intermediate-density liporotein

(IDL). Lipoprotein that is intermediate between very low-density lipoprotein and low-density lipoprotein.

Phospholipid transfer protein

(PLTP). Transfers phospholipids and cholesterol to high-density lipoproteins from very low-density lipoproteins and chylomicrons.

Cholesterol ester transfer protein

(CETP). A circulating protein secreted from the liver. CETP mediates the transfer of triglycerides from low-density lipoprotein and very low-density lipoprotein to high-density lipoprotein in exchange for cholesterol esters.

Lipoprotein lipase

(LPL). Hydrolyses triglycerides in chylomicrons and very low-density lipoproteins to fatty acids and glycerol.

E3 ligase

Substrate recognition enzyme that allows covalent attachment of ubiquitin from E2 ligase to a Lys or Cys residue in the substrate.

Ubiquitylation

Process of attaching one or more ubiquitin molecules to a substrate, thereby targeting the substrate for degradation by the proteosome or lysosome.

E2 ligase

E2 ubiquitin conjugating enzyme that forms an intermediate with ubiquitin in the E1–E2–E3 ubiquitin cascade.

Fatty acid β-oxidation

An enzymatic pathway for metabolizing fatty acids to generate energy.

Farnesol

An intermediate in the cholesterol biosynthetic pathway.

Chylomicrons

Large particles composed of triglycerides, lipoproteins and phospholipids. They are formed in the intestine from dietary components and transported to the periphery, where they are hydrolysed to liberate fatty acids.

db/db

The diabetic gene (db), transmitted as an autosomal recessive trait, encodes for a G-to-T point mutation of the leptin receptor, leading to abnormal splicing and defective signalling of the adipocyte-derived hormone leptin. db/db mice are obese and become hyperphagic soon on weaning.

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