▪ Abstract The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we presen...

The Mechanisms of Action of PPARs

Cholesterol, fatty acids, fat-soluble vitamins, and other lipids present in our diets are not only nutritionally important but serve as precursors for ligands that bind to receptors in the nucleus. To become biologically active, these lipids must first be absorbed by the intestine and transformed by metabolic enzymes before they are delivered to their sites of action in the body. Ultimately, the lipids must be eliminated to maintain a normal physiological state. The need to coordinate this entire lipid-based metabolic signaling cascade raises important questions regarding the mechanisms that govern these pathways. Specifically, what is the nature of communication between these bioactive lipids and their receptors, binding proteins, transporters, and metabolizing enzymes that links them physiologically and speaks to a higher level of metabolic control? Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.

https://science.sciencemag.org/content/sci/294/5548/1866.full.pdf

Nuclear receptors and lipid physiology: opening the X-files.

Highly potent, but poorly water-soluble, drug candidates are common outcomes of contemporary drug discovery programmes and present a number of challenges to drug development - most notably, the issue of reduced systemic exposure after oral administration. However, it is increasingly apparent that formulations containing natural and/or synthetic lipids present a viable means for enhancing the oral bioavailability of some poorly water-soluble, highly lipophilic drugs. This Review details the mechanisms by which lipids and lipidic excipients affect the oral absorption of lipophilic drugs and provides a perspective on the possible future applications of lipid-based delivery systems. Particular emphasis has been placed on the capacity of lipids to enhance drug solubilization in the intestinal milieu, recruit intestinal lymphatic drug transport (and thereby reduce first-pass drug metabolism) and alter enterocyte-based drug transport and disposition.

Lipids and lipid-based formulations: optimizing the oral delivery of lipophilic drugs

Obesity and the related disorders of dyslipidemia and diabetes (components of syndrome X) have become global health epidemics. Over the past decade, the elucidation of key regulators of energy balance and insulin signaling have revolutionized our understanding of fat and sugar metabolism and their intimate link. The three 'lipid-sensing' peroxisome proliferator-activated receptors (PPAR-alpha, PPAR-gamma and PPAR-delta) exemplify this connection, regulating diverse aspects of lipid and glucose homeostasis, and serving as bona fide therapeutic targets. With molecular underpinnings now in place, new pharmacologic approaches to metabolic disease and new questions are emerging.

PPARs and the complex journey to obesity

There are at least two types of cannabinoid receptors (CB1 and CB2). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ9-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB1, non-CB2 established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB1 and/or CB2 receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB3” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB1, non-CB2 pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB3 receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB1 receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB1/CB2 receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB1, non-CB2 cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

https://pharmrev.aspetjournals.org/content/pharmrev/62/4/588.full.pdf

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2

In the past 10 years, specific roles for peroxisome proliferator-activated receptor α (PPARα) and PPARγ have emerged while information defining PPARβ-dependent processes is lacking. PPARs are members of the nuclear receptor superfamily (34). The three PPARs exhibit unique tissue distribution, are encoded by separate genes in all species examined to date, and are designated by the subtypes α, β (δ, NUC1), and γ (14, 18, 34, 47, 48). Acting as regulatory transcription factors, the PPARs heterodimerize with retinoid X receptors and modulate gene expression in target genes containing peroxisome proliferator-responsive elements (PPREs) in response to ligand activation.

The three PPARs have related but distinct activities. Activation of PPARα can occur as a result of cold shock (19), food restriction (26), dietary fatty acids (44), and treatment with the hypolipidemic fibrate class of drugs (31). Peroxisomal and mitochondrial β-oxidizing enzymes, microsomal ω-oxidizing enzymes, hepatic fatty acid binding protein, carnitine palmitoyltransferases, and a number of apolipoproteins are all regulated by PPARα ligands/activators (3, 26, 31, 38, 41, 44). These data, obtained in part from the PPARα-null mouse, provide strong in vivo evidence that PPARα regulates lipid metabolism by regulating gene expression of numerous proteins which are clinically relevant for a number of diseases including diabetes, obesity, and atherosclerosis.

Another PPAR isoform, PPARγ, is required for adipocyte differentiation and regulation of adipocyte-specific genes such as the gene for adipocyte fatty acid binding protein aP2 (47). Similar to PPARα, PPARγ is activated by specific ligands, most notably the thiazolidinedione drugs used for type 2 diabetes therapy (32). The phenotype of a PPARγ-null mouse line is embryo lethal due in part to disrupted placental function (4). Tetraploid rescue experiments to bypass the placental defect confirmed an in vivo role for the receptor in adipogenesis (4). Analysis of heterozygotes and chimeras also established a role for PPARγ in adipocyte function and glucose homeostasis (29, 45). Thus, it is clear from null mouse studies that there are distinct metabolic roles for PPARα and PPARγ.

The function of PPARβ has remained elusive. While PPARβ is ubiquitously expressed, some tissues express relatively higher levels of the mRNA including the brain, adipose tissue, and skin (2, 8). Expression of PPARβ is considerably higher in the developing neural tube and the epidermis during rat development (9). No target genes that are controlled only by PPARβ have been identified, but activators for PPARβ including fatty acids (27), bezafibrate (28), and a furan-conjugated linoleic acid metabolite (39) are reported to activate reporter gene constructs containing PPREs through PPARβ. Despite the lack of a specific PPARβ ligand to induce activation, there are several reports suggesting roles for PPARβ in adipocyte differentiation (5), brain function (51), epidermal differentiation (37), uterine implantation (33), and colon cancer (20). In large part, these studies are correlative associations; definitive proof for PPARβ function requires the use of a null mouse model. In the present study, a PPARβ-null mouse was generated and characterized to identify physiological functions dependent on PPARβ.

Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ)

After incomplete traumatic spinal cord injury (SCI), the spared tissue exhibits abnormal myelination that is associated with reduced or blocked axonal conductance. To examine the molecular basis of the abnormal myelination, we used a standardized rat model of incomplete SCI and compared normal uninjured tissue with that after contusion injury. We evaluated expression of mRNA for myelin proteins using in situ hybridization with oligonucleotide probes to proteolipid protein (PLP), the major protein in central myelin; myelin basic protein (MBP), a major component of central myelin and a minor component of peripheral myelin; and protein zero (P0), the major structural protein of peripheral myelin, as well as myelin transcription factor 1 (MYT1). We found reduced expression of PLP and MBP chronically after SCI in the dorsal, lateral, and ventral white matter both rostral and caudal to the injury epicenter. Detailed studies of PLP at 2 months after injury indicated that the density of expressing cells was normal but mRNA per cell was reduced. In addition, P0, normally restricted to the peripheral nervous system, was expressed both at the epicenter and in lesioned areas at least 4 mm rostral and caudal to it. Thus, after SCI, abnormal myelination of residual axons may be caused, at least in part, by changes in the transcriptional regulation of genes for myelin proteins and by altered distribution of myelin-producing cells. In addition, the expression of MYT1 mRNA and protein seemed to be upregulated after SCI in a pattern suggesting the presence of undifferentiated progenitor cells in the chronically injured cord.

https://www.jneurosci.org/content/jneuro/18/21/8780.full.pdf

Myelin Gene Expression after Experimental Contusive Spinal Cord Injury

Zinc finger transcription factors of the Kruppel-class figure prominently in cell fate specification and differentiation in the nervous system. One of the Kruppel-type genes that was originally cloned from an oligodendrocyte library by virtue of its homology with the prototypic Kruppel motif is the rat rKr2 gene (Pott et al., 1995). In primary cultures of rat glial cells, the rKr2 protein was only present in the oligodendrocyte lineage, predominantly in progenitors. Ninety percent of A2B5(+) oligodendrocyte progenitors displayed rKr2 immunoreactivity, while most MBP(+) oligodendrocytes lacked detectable rKr2. A similar pattern was found in vivo, in which the peak expression of rKr2 in the oligodendrocyte lineage of rats coincided with the wave of progenitor proliferation in early postnatal life. The subventricular zone, a source of neuronal and glial progenitors, displayed intense staining for rKr2 at late embryonic and postnatal stages. In the adult, cells within the remnants of this germinal zone continued to express rKr2 protein strongly. Some populations of mature neurons also displayed rKr2 immunostaining. Astrocytes and microglia were not labeled with the polyclonal anti-rKr2 antibody in vitro or in vivo. At all developmental stages, the rKr2 protein was localized to the nucleus. The stage-specific expression pattern and the subcellular localization of rKr2 recommend a role for this Kruppel-type gene in the progression of neural stem cells and in the early development of the oligodendrocyte lineage.

Wen Li

Papers

Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ)

Myelin Gene Expression after Experimental Contusive Spinal Cord Injury

Expression of the Krüppel-type zinc finger protein rKr2 in the developing nervous system†