Susanna S.T. Lee

Bio: Susanna S.T. Lee is an academic researcher from The Chinese University of Hong Kong. The author has contributed to research in topics: Peroxisome proliferator-activated receptor & Peroxisome proliferator-activated receptor gamma. The author has an hindex of 15, co-authored 29 publications receiving 4749 citations. Previous affiliations of Susanna S.T. Lee include National Institutes of Health.

Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators.

Abstract: To gain insight into the function of peroxisome proliferator-activated receptor (PPAR) isoforms in rodents, we disrupted the ligand-binding domain of the alpha isoform of mouse PPAR (mPPAR alpha) by homologous recombination. Mice homozygous for the mutation lack expression of mPPAR alpha protein and yet are viable and fertile and exhibit no detectable gross phenotypic defects. Remarkably, these animals do not display the peroxisome proliferator pleiotropic response when challenged with the classical peroxisome proliferators, clofibrate and Wy-14,643. Following exposure to these chemicals, hepatomegaly, peroxisome proliferation, and transcriptional-activation of target genes were not observed. These results clearly demonstrate that mPPAR alpha is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators. mPPAR alpha-deficient animals should prove useful to further investigate the role of this receptor in hepatocarcinogenesis, fatty acid metabolism, and cell cycle regulation.

Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor

Abstract: The aryl hydrocarbon (Ah) receptor (AHR) mediates many carcinogenic and teratogenic effects of environmentally toxic chemicals such as dioxin. An AHR-deficient (Ahr-/-) mouse line was constructed by homologous recombination in embryonic stem cells. Almost half of the mice died shortly after birth, whereas survivors reached maturity and were fertile. The Ahr-/- mice showed decreased accumulation of lymphocytes in the spleen and lymph nodes, but not in the thymus. The livers of Ahr-/- mice were reduced in size by 50 percent and showed bile duct fibrosis Ahr-/- mice were also nonresponsive with regard to dioxin-mediated induction of genes encoding enzymes that catalyze the metabolism of foreign compounds. Thus, the AHR plays an important role in the development of the liver and the immune system.

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

Abstract: 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.

The gut microbiota as an environmental factor that regulates fat storage

Abstract: New therapeutic targets for noncognitive reductions in energy intake, absorption, or storage are crucial given the worldwide epidemic of obesity. The gut microbial community (microbiota) is essential for processing dietary polysaccharides. We found that conventionalization of adult germ-free (GF) C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake. Studies of GF and conventionalized mice revealed that the microbiota promotes absorption of monosaccharides from the gut lumen, with resulting induction of de novo hepatic lipogenesis. Fasting-induced adipocyte factor (Fiaf), a member of the angiopoietin-like family of proteins, is selectively suppressed in the intestinal epithelium of normal mice by conventionalization. Analysis of GF and conventionalized, normal and Fiaf knockout mice established that Fiaf is a circulating lipoprotein lipase inhibitor and that its suppression is essential for the microbiota-induced deposition of triglycerides in adipocytes. Studies of Rag1-/- animals indicate that these host responses do not require mature lymphocytes. Our findings suggest that the gut microbiota is an important environmental factor that affects energy harvest from the diet and energy storage in the host. Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AY 667702--AY 668946).

Peroxisome proliferator-activated receptors: nuclear control of metabolism.

Abstract: I. Introduction II. Molecular Aspects A. PPAR isotypes: identity, genomic organization and chromosomal localization B. DNA binding properties C. PPAR ligand-binding properties D. Alternative pathways for PPAR activation E. PPAR-mediated transactivation properties III. Physiological Aspects A. Differential expression of PPAR mRNAs B. PPAR target genes and functions in fatty acid metabolism C. PPARs and control of inflammatory responses D. PPARs and atherosclerosis E. PPARs and the development of the fetal epidermal permeability barrier F. PPARs, carcinogenesis, and control of the cell cycle IV. Conclusions

The Mechanisms of Action of PPARs

Abstract: ▪ 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...

Metabolism and Functions of Lipids and Fatty Acids in Teleost Fish

Abstract: Lipids and their constituent fatty acids are, along with proteins, the major organic constituents of fish, and they play major roles as sources of metabolic energy for growth including reproduction and movement, including migration. Furthermore, the fatty acids of fish lipids are rich in ω3 long chain, highly unsaturated fatty acids (n-3 HUFA) that have particularly important roles in animal nutrition, including fish and human nutrition, reflecting their roles in critical physiological processes. Indeed, fish are the most important food source of these vital nutrients for man. Thus, the longstanding interest in fish lipids stems from their abundance and their uniqueness. This review attempts to summarize our present state of knowledge of various aspects of the basic biochemistry, metabolism, and functions of fatty acids, and the lipids they constitute part of, in fish, seeking where possible to relate that understanding as much to fish in their natural environment as to farmed fish. In doing so, it highli...