Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease, and the fastest-growing reason for liver transplantation. It is estimated that more than half of patients with type 2 diabetes (T2D) have NAFLD, and even patients with type 1 diabetes have higher risk of developing fatty liver than people without diabetes. There are currently no drugs approved to treat NAFLD. Even more vexing, novel therapeutics for T2D that increase liver insulin sensitivity generally increase fat deposition in the liver, creating a vicious cycle that paradoxically worsens the liver disease. Now, diabetes investigator Utpal Pajvani, M.D., Ph.D., and his team of researchers at the Naomi Berrie Diabetes Center, led by KyeongJin Kim, Ph.D., have discovered that a simple protein, originally thought to do one job, has the capability of doing something completely different—and quite extraordinary. “We found, for the first time, a pathway that prevents insulin or insulin sensitizing therapy from causing fatty liver, without getting rid of the favorable effects of insulin to reduce blood sugar,” said Dr. Pajvani, an Assistant Professor of Medicine at Columbia University In a paper released in the January 2016 issue of Nature Communications. Drs. Kim and Pajvani document the secret life of a protein called Raptor that exists within a protein complex called mTORC1 which is involved in everything from cell growth and cell differentiation to cell usage of glucose or lipids. “mTORC1 is one of the most-studied biological pathways, since it has so many functions, and has been implicated not only in the development of diabetes and fatty liver disease, but also cancer,” said Dr. Pajvani. Raptor has long been known to be the regulatory component of mTORC1’s function to phosphorylate other proteins, but Dr. Pajvani’s group reports for the first time that Raptor not only exists independently from mTORC1, but has the capacity in its free state to reverse fatty liver in mice by stabilizing another protein called PHLPP2, which in turn turns off insulin signaling. Aging or obesity normally cause PHLPP2 to degrade, leaving in its wake “a chronic, smoldering insulin signaling that results in fatty liver. Free Raptor, through protecting PHLPP2 from degradation, turns off the insulin signaling.” While the nomenclature of the protein complex is difficult to the uninitiated (his paper is entitled “mTORC1-independent Raptor prevents hepatic steatosis by stabilizing PHLPP2”) Dr. Pajvani’s explanation of his discovery as it played out in laboratory mice, is clear, concise and compelling. “As it turns out, young, healthy mice, (and we assume, young, healthy people) have a lot of this free Raptor. As mice age or get fat, free Raptor disappears. When free Raptor disappears, mice get fatty liver. If you give them back free Raptor, fatty liver goes away but leaves insulin’s ability to lower blood sugar intact.” Dr. Pajvani’s work is big news for the other scientists who study insulin resistance, diabetes and other metabolic disorders, but may have stronger impact still in far-flung domains such as cancer biology. This same pathway is targeted by cancer researchers and immunologists, and mTORC1 inhibitors are already in clinical use as chemotherapy for cancer patients and as an immunosuppressant for organ transplant patients. “The role of free Raptor that we discovered is not likely to be limited to hepatic lipid metabolism to prevent age and obesity induced fatty liver,” said Dr. Pajvani. “If we can figure out what frees Raptor from mTOR, we may have accidentally discovered a better means to modulate this very important pathway in order to design a more effective cancer or immunosuppressant drug.” But, we’re some time away from this, he cautions: “All we have are genetic mouse models – we have to prove the relevance of this free Raptor-PHLPP2 axis in people, which may give impetus for pharmaceutical companies to develop a drug to do the same.”
Westerterp M.,Columbia University |
Westerterp M.,University of Groningen |
Tsuchiya K.,Naomi Berrie Diabetes Center |
Tsuchiya K.,Tokyo Medical and Dental University |
And 10 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2016
Objective-Plasma high-density lipoproteins have several putative antiatherogenic effects, including preservation of endothelial functions. This is thought to be mediated, in part, by the ability of high-density lipoproteins to promote cholesterol efflux from endothelial cells (ECs). The ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1) interact with high-density lipoproteins to promote cholesterol efflux from ECs. To determine the impact of endothelial cholesterol efflux pathways on atherogenesis, we prepared mice with endothelium-specific knockout of Abca1 and Abcg1. Approach and Results-Generation of mice with EC-ABCA1 and ABCG1 deficiency required crossbreeding Abca1fl/flAbcg1fl/flLdlr-/- mice with the Tie2Cre strain, followed by irradiation and transplantation of Abca1fl/flAbcg1fl/fl bone marrow to abrogate the effects of macrophage ABCA1 and ABCG1 deficiency induced by Tie2Cre. After 20 to 22 weeks of Western-Type diet, both single EC-Abca1 and Abcg1 deficiency increased atherosclerosis in the aortic root and whole aorta. Combined EC-Abca1/g1 deficiency caused a significant further increase in lesion area at both sites. EC-Abca1/g1 deficiency dramatically enhanced macrophage lipid accumulation in the branches of the aorta that are exposed to disturbed blood flow, decreased aortic endothelial NO synthase activity, and increased monocyte infiltration into the atherosclerotic plaque. Abca1/g1 deficiency enhanced lipopolysaccharide-induced inflammatory gene expression in mouse aortic ECs, which was recapitulated by ABCG1 deficiency in human aortic ECs. Conclusions-These studies provide direct evidence that endothelial cholesterol efflux pathways mediated by ABCA1 and ABCG1 are nonredundant and atheroprotective, reflecting preservation of endothelial NO synthase activity and suppression of endothelial inflammation, especially in regions of disturbed arterial blood flow. © 2016 American Heart Association, Inc. Source
Li P.,University of Alabama at Birmingham |
Tiwari H.K.,University of Alabama at Birmingham |
Lin W.-Y.,National Taiwan University |
Allison D.B.,University of Alabama at Birmingham |
And 6 more authors.
International Journal of Obesity | Year: 2014
Objective: Obesity, which is frequently associated with diabetes, hypertension and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). Methods: We reanalyzed 355 common genetic variants of 30 candidate genes in seven molecular pathways related to obesity in 1982 unrelated European Americans from the New York Cancer Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates, including age, age 2, gender and diabetes status. The single-nucleotide polymorphisms (SNPs) were modeled as additive effects. Results: With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: ghrelin (GHRL; rs35683), agouti-related peptide (AGRP; rs5030980), carboxypeptidase E (CPE; rs1946816 and rs4481204), glucagon-like peptide-1 receptor (GLP1R; rs2268641), serotonin receptors (HTR2A; rs912127), neuropeptide Y receptor (NPY5R;Y5R1c52), suppressor of cytokine signaling 3 (SOCS3; rs4969170) and signal transducer and activator of transcription 3 (STAT3; rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. Conclusion: Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake, and thus these associations are mechanistically plausible in this context. © 2014 Macmillan Publishers Limited All rights reserved. Source
Wakae-Takada N.,Columbia University |
Wakae-Takada N.,Naomi Berrie Diabetes Center |
Xuan S.,Columbia University |
Watanabe K.,Columbia University |
And 4 more authors.
Diabetologia | Year: 2013
Aims/hypothesis: In rodents and humans, the rate of beta cell proliferation declines rapidly after birth; formation of the islets of Langerhans begins perinatally and continues after birth. Here, we tested the hypothesis that increasing levels of E-cadherin during islet formation mediate the decline in beta cell proliferation rate by contributing to a reduction of nuclear β-catenin and D-cyclins. Methods: We examined E-cadherin, nuclear β-catenin, and D-cyclin levels, as well as cell proliferation during in vitro and in vivo formation of islet cell aggregates, using β-TC6 cells and transgenic mice with green fluorescent protein (GFP)-labelled beta cells, respectively. We tested the role of E-cadherin using antisense-mediated reductions of E-cadherin in β-TC6 cells, and mice segregating for a beta cell-specific E-cadherin knockout (Ecad [also known as Cdh1] βKO). Results: In vitro, pseudo-islets of β-TC6 cells displayed increased E-cadherin but decreased nuclear β-catenin and cyclin D2, and reduced rates of cell proliferation, compared with monolayers. Antisense knockdown of E-cadherin increased cell proliferation and levels of cyclins D1 and D2. After birth, beta cells showed increased levels of E-cadherin, but decreased levels of D-cyclin, whereas islets of Ecad βKO mice showed increased levels of D-cyclins and nuclear β-catenin, as well as increased beta cell proliferation. These islets were significantly larger than those of control mice and displayed reduced levels of connexin 36. These changes correlated with reduced insulin response to ambient glucose, both in vitro and in vivo. Conclusions/ interpretation: The findings support our hypothesis by indicating an important role of E-cadherin in the control of beta cell mass and function. © 2013 Springer-Verlag Berlin Heidelberg. Source