Emerging new paradigms for ABCG transporters

Every cell is separated from its external environment by a lipid membrane. Survival depends on the regulated and selective transport of nutrients, waste products and regulatory molecules across these membranes, a process that is often mediated by integral membrane proteins. The largest and most diverse of these membrane transport systems is the ATP binding cassette (ABC) family of membrane transport proteins. The ABC family is a large evolutionary conserved family of transmembrane proteins (> 250 members) present in all phyla, from bacteria to Homo sapiens, which require energy in the form of ATP hydrolysis to transport substrates against concentration gradients. In prokaryotes the majority of ABC transporters are involved in the transport of nutrients and other macromolecules into the cell. In eukaryotes, with the exception of the cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7), ABC transporters mobilize substrates from the cytoplasm out of the cell or into specific intracellular organelles. This review focuses on the members of the ABCG subfamily of transporters, which are conserved through evolution in multiple taxa. As discussed below, these proteins participate in multiple cellular homeostatic processes, and functional mutations in some of them have clinical relevance in humans

Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis

Summary: As an important regulator of macrophage cholesterol efflux and HDL biogenesis, miR-33 is a promising target for treatment of atherosclerosis, and numerous studies demonstrate that inhibition of miR-33 increases HDL levels and reduces plaque burden. However, important questions remain about how miR-33 impacts atherogenesis, including whether this protection is primarily due to direct effects on plaque macrophages or regulation of lipid metabolism in the liver. We demonstrate that miR-33 deficiency in Ldlr−/− mice promotes obesity, insulin resistance, and hyperlipidemia but does not impact plaque development. We further assess how loss of miR-33 or addition of miR-33b in macrophages and other hematopoietic cells impact atherogenesis. Macrophage-specific loss of miR-33 decreases lipid accumulation and inflammation under hyperlipidemic conditions, leading to reduced plaque burden. Therefore, the pro-atherogenic effects observed in miR-33-deficient mice are likely counterbalanced by protective effects in macrophages, which may be the primary mechanism through which anti-miR-33 therapies reduce atherosclerosis. : miR-33a and miR-33b, the miR-33 family of miRNAs, are important regulators of reverse cholesterol transport and atherosclerosis. Price et al. have developed genetic models to explore the specific roles of miR-33a and miR-33b in atherosclerotic plaque formation. Their findings highlight both the utility and potential issues involved in anti-miR-33 therapies. Keywords: Atherosclerosis, miR-33, HDL-C, metabolism, cholestero

ABCG1 regulates pulmonary surfactant metabolism in mice and men

Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant. Surfactant synthesis and secretion are restricted to epithelial type 2 (T2) pneumocytes (also called T2 cells). Clearance of surfactant is dependent upon T2 cells and macrophages. ABCG1 is highly expressed in both T2 cells and macrophages. ABCG1-deficient mice accumulate surfactant, lamellar body-loaded T2 cells, lipid-loaded macrophages, B-1 lymphocytes, and immunoglobulins, clearly demonstrating that ABCG1 has a critical role in pulmonary homeostasis. We identify a variant in the ABCG1 promoter in patients with PAP that results in impaired activation of ABCG1 by the liver X receptor α, suggesting that ABCG1 basal expression and/or induction in response to sterol/lipid loading is essential for normal lung function. We generated mice lacking ABCG1 specifically in either T2 cells or macrophages to determine the relative contribution of these cell types on surfactant lipid homeostasis. These results establish a critical role for T2 cell ABCG1 in controlling surfactant and overall lipid homeostasis in the lung and in the pathogenesis of human lung disease

Akt-mediated FoxO1 inhibition is required for liver regeneration

Understanding the hepatic regenerative process has clinical interest as the effectiveness of many treatments for chronic liver diseases is conditioned by efficient liver regeneration. Experimental evidence points to the need for a temporal coordination between cytokines, growth factors, and metabolic signaling pathways to enable successful liver regeneration. One intracellular mediator that acts as a signal integration node for these processes is the serine-threonine kinase Akt/protein kinase B (Akt). To investigate the contribution of Akt during hepatic regeneration, we performed partial hepatectomy in mice lacking Akt1, Akt2, or both isoforms. We found that absence of Akt1 or Akt2 does not influence liver regeneration after partial hepatectomy. However, hepatic-specific Akt1 and Akt2 null mice show impaired liver regeneration and increased mortality. The major abnormal cellular events observed in total Akt-deficient livers were a marked reduction in cell proliferation, cell hypertrophy, glycogenesis, and lipid droplet formation. Most importantly, liver-specific deletion of FoxO1, a transcription factor regulated by Akt, rescued the hepatic regenerative capability in Akt1-deficient and Akt2- deficient mice and normalized the cellular events associated with liver regeneration. Conclusion: The Akt-FoxO1 signaling pathway plays an essential role during liver regeneration

Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis.

Previous work has reported the important links between cellular bioenergetics and the development of chronic kidney disease, highlighting the potential for targeting metabolic functions to regulate disease progression. More recently, it has been shown that alterations in fatty acid oxidation (FAO) can have an important impact on the progression of kidney disease. In this work, we demonstrate that loss of miR-33, an important regulator of lipid metabolism, can partially prevent the repression of FAO in fibrotic kidneys and reduce lipid accumulation. These changes were associated with a dramatic reduction in the extent of fibrosis induced in 2 mouse models of kidney disease. These effects were not related to changes in circulating leukocytes because bone marrow transplants from miR-33–deficient animals did not have a similar impact on disease progression. Most important, targeted delivery of miR-33 peptide nucleic acid inhibitors to the kidney and other acidic microenvironments was accomplished using pH low insertion peptides as a carrier. This was effective at both increasing the expression of factors involved in FAO and reducing the development of fibrosis. Together, these findings suggest that miR-33 may be an attractive therapeutic target for the treatment of chronic kidney diseaseThis work was supported by grants from the NIH (R35HL135820 to CFH, R01HL105945 and R01HL135012 to YS, GM073857 to OAA and YKR, and P30 DK079310 to the George M. O’Brien Kidney Center at Yale), the American Heart Association (16EIA27550005 to CFH, 16GRNT26420047 to YS, and 17SDG33110002 to NR), the Foundation Leducq Transatlantic Network of Excellence in Cardiovascular Research MicroRNA-based Therapeutic Strategies in Vascular Disease (to CFH), and the University of Connecticut START PPOC award (to RB) Ministerio de Economia y Competitividad (MINECO) (SAF2015-66107-R to SL), Carlos III Health Institute (ISCIII) European Regional Development Fund (PI17/01513 to DRP); cofunded by the European Regional Development Fund; and supported by Instituto de Salud Carlos III REDinREN RD12/0021/0009 and RD16/0009/0016 (to SL and DRP), Comunidad de Madrid “NOVELREN” B2017/BMD3751 (to SL and DRP), a grant-in-aid from the Spanish Society of Nephrology (Fundacion Senefro 2017 to SL), and Fundacion Renal “Inigo Alvarez de Toledo” (to SL), all from Spain. The Centro de Biologia Molecular “Severo Ochoa” (CBMSO) receives institutional support from Fundacion “Ramon Areces.” SL was supported by the “Salvador de Madariaga” grant PRX15/00119 from the Spanish Ministry of Educacion, Cultura y Deport