Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice
Acid sphingomyelinase plays important roles in ceramide homeostasis, which has been proposed to be linked to insulin resistance. To test this association in vivo, acid sphingomyelinase deletion (asm–/–) was transferred to mice lacking the low density lipoprotein receptor (ldlr–/–), and then offsprin...
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creator | Deevska, Gergana M. Rozenova, Krassimira A. Giltiay, Natalia V. Chambers, Melissa A. White, James Boyanovsky, Boris B. Wei, Jia Daugherty, Alan Smart, Eric J. Reid, Michael B. Merrill, Alfred H. Nikolova-Karakashian, Mariana |
description | Acid sphingomyelinase plays important roles in ceramide homeostasis, which has been proposed to be linked to insulin resistance. To test this association in vivo, acid sphingomyelinase deletion (asm–/–) was transferred to mice lacking the low density lipoprotein receptor (ldlr–/–), and then offsprings were placed on control or modified (enriched in saturated fat and cholesterol) diets for 10 weeks. The modified diet caused hypercholesterolemia in all genotypes; however, in contrast to asm+/+/ldlr–/–, the acid sphingomyelinase-deficient littermates did not display hepatic triacylglyceride accumulation, although sphingomyelin and other sphingolipids were substantially elevated, and the liver was enlarged. asm–/–/ldlr–/– mice on a modified diet did not accumulate body fat and were protected against diet-induced hyperglycemia and insulin resistance. Experiments with hepatocytes revealed that acid sphingomyelinase regulates the partitioning of the major fatty acid in the modified diet, palmitate, into two competitive and inversely related pools, triacylglycerides and sphingolipids, apparently via modulation of serine palmitoyltransferase, a rate-limiting enzyme in de novo sphingolipid synthesis. These studies provide evidence that acid sphingomyelinase activity plays an essential role in the regulation of glucose metabolism by regulating the hepatic accumulation of triacylglycerides and sphingolipids during consumption of a diet rich in saturated fats. |
doi_str_mv | 10.1074/jbc.M807800200 |
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To test this association in vivo, acid sphingomyelinase deletion (asm–/–) was transferred to mice lacking the low density lipoprotein receptor (ldlr–/–), and then offsprings were placed on control or modified (enriched in saturated fat and cholesterol) diets for 10 weeks. The modified diet caused hypercholesterolemia in all genotypes; however, in contrast to asm+/+/ldlr–/–, the acid sphingomyelinase-deficient littermates did not display hepatic triacylglyceride accumulation, although sphingomyelin and other sphingolipids were substantially elevated, and the liver was enlarged. asm–/–/ldlr–/– mice on a modified diet did not accumulate body fat and were protected against diet-induced hyperglycemia and insulin resistance. Experiments with hepatocytes revealed that acid sphingomyelinase regulates the partitioning of the major fatty acid in the modified diet, palmitate, into two competitive and inversely related pools, triacylglycerides and sphingolipids, apparently via modulation of serine palmitoyltransferase, a rate-limiting enzyme in de novo sphingolipid synthesis. These studies provide evidence that acid sphingomyelinase activity plays an essential role in the regulation of glucose metabolism by regulating the hepatic accumulation of triacylglycerides and sphingolipids during consumption of a diet rich in saturated fats.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M807800200</identifier><identifier>PMID: 19074137</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Food, Formulated - adverse effects ; Glucose - metabolism ; Hepatocytes - enzymology ; Hyperglycemia - chemically induced ; Hyperglycemia - enzymology ; Insulin Resistance - genetics ; Lipids and Lipoproteins: Metabolism, Regulation, and Signaling ; Liver - enzymology ; Mice ; Mice, Knockout ; Palmitates - metabolism ; Receptors, LDL - genetics ; Receptors, LDL - metabolism ; Serine C-Palmitoyltransferase - genetics ; Serine C-Palmitoyltransferase - metabolism ; Sphingolipids - metabolism ; Sphingomyelin Phosphodiesterase - deficiency ; Sphingomyelin Phosphodiesterase - metabolism ; Triglycerides - genetics ; Triglycerides - metabolism</subject><ispartof>The Journal of biological chemistry, 2009-03, Vol.284 (13), p.8359-8368</ispartof><rights>2009 © 2009 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><rights>Copyright © 2009, The American Society for Biochemistry and Molecular Biology, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c520t-192e8347341f8a7108c1a4e9b3e2b9357eb54932362b7cee019237bbdb65b8703</citedby><cites>FETCH-LOGICAL-c520t-192e8347341f8a7108c1a4e9b3e2b9357eb54932362b7cee019237bbdb65b8703</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659194/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659194/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19074137$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Deevska, Gergana M.</creatorcontrib><creatorcontrib>Rozenova, Krassimira A.</creatorcontrib><creatorcontrib>Giltiay, Natalia V.</creatorcontrib><creatorcontrib>Chambers, Melissa A.</creatorcontrib><creatorcontrib>White, James</creatorcontrib><creatorcontrib>Boyanovsky, Boris B.</creatorcontrib><creatorcontrib>Wei, Jia</creatorcontrib><creatorcontrib>Daugherty, Alan</creatorcontrib><creatorcontrib>Smart, Eric J.</creatorcontrib><creatorcontrib>Reid, Michael B.</creatorcontrib><creatorcontrib>Merrill, Alfred H.</creatorcontrib><creatorcontrib>Nikolova-Karakashian, Mariana</creatorcontrib><title>Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Acid sphingomyelinase plays important roles in ceramide homeostasis, which has been proposed to be linked to insulin resistance. To test this association in vivo, acid sphingomyelinase deletion (asm–/–) was transferred to mice lacking the low density lipoprotein receptor (ldlr–/–), and then offsprings were placed on control or modified (enriched in saturated fat and cholesterol) diets for 10 weeks. The modified diet caused hypercholesterolemia in all genotypes; however, in contrast to asm+/+/ldlr–/–, the acid sphingomyelinase-deficient littermates did not display hepatic triacylglyceride accumulation, although sphingomyelin and other sphingolipids were substantially elevated, and the liver was enlarged. asm–/–/ldlr–/– mice on a modified diet did not accumulate body fat and were protected against diet-induced hyperglycemia and insulin resistance. Experiments with hepatocytes revealed that acid sphingomyelinase regulates the partitioning of the major fatty acid in the modified diet, palmitate, into two competitive and inversely related pools, triacylglycerides and sphingolipids, apparently via modulation of serine palmitoyltransferase, a rate-limiting enzyme in de novo sphingolipid synthesis. 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Rozenova, Krassimira A. ; Giltiay, Natalia V. ; Chambers, Melissa A. ; White, James ; Boyanovsky, Boris B. ; Wei, Jia ; Daugherty, Alan ; Smart, Eric J. ; Reid, Michael B. ; Merrill, Alfred H. ; Nikolova-Karakashian, Mariana</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c520t-192e8347341f8a7108c1a4e9b3e2b9357eb54932362b7cee019237bbdb65b8703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Food, Formulated - adverse effects</topic><topic>Glucose - metabolism</topic><topic>Hepatocytes - enzymology</topic><topic>Hyperglycemia - chemically induced</topic><topic>Hyperglycemia - enzymology</topic><topic>Insulin Resistance - genetics</topic><topic>Lipids and Lipoproteins: Metabolism, Regulation, and Signaling</topic><topic>Liver - enzymology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Palmitates - metabolism</topic><topic>Receptors, LDL - genetics</topic><topic>Receptors, LDL - metabolism</topic><topic>Serine C-Palmitoyltransferase - genetics</topic><topic>Serine C-Palmitoyltransferase - metabolism</topic><topic>Sphingolipids - metabolism</topic><topic>Sphingomyelin Phosphodiesterase - deficiency</topic><topic>Sphingomyelin Phosphodiesterase - metabolism</topic><topic>Triglycerides - genetics</topic><topic>Triglycerides - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Deevska, Gergana M.</creatorcontrib><creatorcontrib>Rozenova, Krassimira A.</creatorcontrib><creatorcontrib>Giltiay, Natalia V.</creatorcontrib><creatorcontrib>Chambers, Melissa A.</creatorcontrib><creatorcontrib>White, James</creatorcontrib><creatorcontrib>Boyanovsky, Boris B.</creatorcontrib><creatorcontrib>Wei, Jia</creatorcontrib><creatorcontrib>Daugherty, Alan</creatorcontrib><creatorcontrib>Smart, Eric J.</creatorcontrib><creatorcontrib>Reid, Michael B.</creatorcontrib><creatorcontrib>Merrill, Alfred H.</creatorcontrib><creatorcontrib>Nikolova-Karakashian, Mariana</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Deevska, Gergana M.</au><au>Rozenova, Krassimira A.</au><au>Giltiay, Natalia V.</au><au>Chambers, Melissa A.</au><au>White, James</au><au>Boyanovsky, Boris B.</au><au>Wei, Jia</au><au>Daugherty, Alan</au><au>Smart, Eric J.</au><au>Reid, Michael B.</au><au>Merrill, Alfred H.</au><au>Nikolova-Karakashian, Mariana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2009-03-27</date><risdate>2009</risdate><volume>284</volume><issue>13</issue><spage>8359</spage><epage>8368</epage><pages>8359-8368</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Acid sphingomyelinase plays important roles in ceramide homeostasis, which has been proposed to be linked to insulin resistance. To test this association in vivo, acid sphingomyelinase deletion (asm–/–) was transferred to mice lacking the low density lipoprotein receptor (ldlr–/–), and then offsprings were placed on control or modified (enriched in saturated fat and cholesterol) diets for 10 weeks. The modified diet caused hypercholesterolemia in all genotypes; however, in contrast to asm+/+/ldlr–/–, the acid sphingomyelinase-deficient littermates did not display hepatic triacylglyceride accumulation, although sphingomyelin and other sphingolipids were substantially elevated, and the liver was enlarged. asm–/–/ldlr–/– mice on a modified diet did not accumulate body fat and were protected against diet-induced hyperglycemia and insulin resistance. Experiments with hepatocytes revealed that acid sphingomyelinase regulates the partitioning of the major fatty acid in the modified diet, palmitate, into two competitive and inversely related pools, triacylglycerides and sphingolipids, apparently via modulation of serine palmitoyltransferase, a rate-limiting enzyme in de novo sphingolipid synthesis. These studies provide evidence that acid sphingomyelinase activity plays an essential role in the regulation of glucose metabolism by regulating the hepatic accumulation of triacylglycerides and sphingolipids during consumption of a diet rich in saturated fats.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19074137</pmid><doi>10.1074/jbc.M807800200</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Food, Formulated - adverse effects Glucose - metabolism Hepatocytes - enzymology Hyperglycemia - chemically induced Hyperglycemia - enzymology Insulin Resistance - genetics Lipids and Lipoproteins: Metabolism, Regulation, and Signaling Liver - enzymology Mice Mice, Knockout Palmitates - metabolism Receptors, LDL - genetics Receptors, LDL - metabolism Serine C-Palmitoyltransferase - genetics Serine C-Palmitoyltransferase - metabolism Sphingolipids - metabolism Sphingomyelin Phosphodiesterase - deficiency Sphingomyelin Phosphodiesterase - metabolism Triglycerides - genetics Triglycerides - metabolism |
title | Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice |
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