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Review
. 2008 Sep;8(4):329-37.
doi: 10.1016/j.mito.2008.02.001. Epub 2008 Feb 26.

Nuclear receptors, mitochondria and lipid metabolism

William A Alaynick  1
Affiliations
Review

Nuclear receptors, mitochondria and lipid metabolism

William A Alaynick. Mitochondrion. 2008 Sep.

Abstract

Lipid metabolism is a continuum from emulsification and uptake of lipids in the intestine to cellular uptake and transport to compartments such as mitochondria. Whether fats are shuttled into lipid droplets in adipose tissue or oxidized in mitochondria and peroxisomes depends on metabolic substrate availability, energy balance and endocrine signaling of the organism. Several members of the nuclear hormone receptor superfamily are lipid-sensing factors that affect all aspects of lipid metabolism. The physiologic actions of glandular hormones (e.g. thyroid, mineralocorticoid and glucocorticoid), vitamins (e.g. vitamins A and D) and reproductive hormones (e.g. progesterone, estrogen and testosterone) and their cognate receptors are well established. The peroxisome-proliferator activated receptors (PPARs) and liver X receptors (LXRs), acting in concert with PPARgamma Coactivator 1alpha (PGC-1alpha), have been shown to regulate insulin sensitivity and lipid handling. These receptors are the focus of intense pharmacologic studies to expand the armamentarium of small molecule ligands to treat diabetes and the metabolic syndrome (hypertension, insulin resistance, hyperglycemia, dyslipidemia and obesity). Recently, additional partners of PGC-1alpha have moved to the forefront of metabolic research, the estrogen-related receptors (ERRs). Although no endogenous ligands for these receptors have been identified, phenotypic analyses of knockout mouse models demonstrate an important role for these molecules in substrate sensing and handling as well as mitochondrial function.

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Figures

Figure 1
Figure 1. The Nuclear Receptor Superfamily
Nuclear hormone receptors can be divided into Endocrine, Adopted Orphan and Orphan subfamilies. The Endocrine receptors have high affinity ligands that are present in nanomolar concentrations, while Adopted orphan receptors have ligands present in the micromolar range. No physiologic ligands have been identified for the orphan receptors. Nuclear receptors share a common arrangement of an amino terminal Activation Function 1 (AF1), a DNA-Binding Domain (DBD), a Ligand Binding Domain (LBD) and a carboxy-terminal Activation Function 2 (AF2). Adapted from Chawla et al. 2001.
Figure 2
Figure 2. Nuclear Receptor Regulation of Metabolic Enzymes
The PPARs, ERRs and LXRs can influence the expression of several genes involved in lipid metabolism. Regulated processes include lipoprotein metabolism, fatty acid uptake, shuttling into mitochondria and fatty acid oxidation. Color-coded circles indicate regulation by a given receptor. I-IV, Electron transport chain complexes; ACADM, acyl-Coenzyme A dehydrogenase, C-4 to C-12 straight chain; ACOX, acyl-Coenzyme A oxidase; ANT, adenine nucleotide translocator; APOA1, apolipoprotein A-I; APOE, apolipoprotein E; CD36, scavenger receptor class B; CKMT2, creatine kinase, mitochondrial 2; CPT-1, carnitine palmitoyltransferase; CS, citrate synthase; DGAT, diacylglycerol O-acyltransferase; FABP, fatty-acid binding protein; FASN, fatty-acid synthase; HADHA, trifunctional protein, alpha subunit; HADHB, trifunctional protein, beta subunit; LDH, lactate dehydrogenase; LDLR, low density lipoprotein receptor; LPL, lipoprotein lipase; MDH1, malate dehydrogenase; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase. Adapted from Alaynick et al. 2007.
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