Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice

Deevska, Gergana M.; Rozenova, Krassimira A.; Giltiay, Natalia V.; Chambers, Melissa; White, James P.; Boyanovsky, Boris B.; Wang, Jia; Daugherty, Alan; Smart, Elizabeth; Reid, Michael B.; Merrill, Alfred H.; Nikolova‐Karakashian, Mariana

doi:10.1074/jbc.m807800200

Cited by 83 publications

(102 citation statements)

References 35 publications

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“…1A) (22). A metabolic interaction between sphingolipid and TAG synthesis has been inferred from previous studies in mice with simultaneous deletions of the acid sphingomyelinase and LDL receptor genes (23). In this case, the absence of acid sphingomyelinase was believed to cause a decrease in the rate of sphingomyelin synthesis, resulting in less DAG and TAG accumulation in liver, together with lower serum lipoprotein levels.…”

Section: Discussionmentioning

confidence: 85%

Sphingosine 1-Phosphate Lyase Deficiency Disrupts Lipid Homeostasis in Liver

Bektas

Allende

Lee

et al. 2010

Journal of Biological Chemistry

181

198

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The cleavage of sphingoid base phosphates by sphingosine-1-phosphate (S1P) lyase to produce phosphoethanolamine and a fatty aldehyde is the final degradative step in the sphingolipid metabolic pathway. We have studied mice with an inactive S1P lyase gene and have found that, in addition to the expected increase of sphingoid base phosphates, other sphingolipids (including sphingosine, ceramide, and sphingomyelin) were substantially elevated in the serum and/or liver of these mice. This latter increase is consistent with a reutilization of the sphingosine backbone for sphingolipid synthesis due to its inability to exit the sphingolipid metabolic pathway. Furthermore, the S1P lyase deficiency resulted in changes in the levels of serum and liver lipids not directly within the sphingolipid pathway, including phospholipids, triacyglycerol, diacylglycerol, and cholesterol. Even though lipids in serum and lipid storage were elevated in liver, adiposity was reduced in the S1P lyasedeficient mice. Microarray analysis of lipid metabolism genes in liver showed that the S1P lyase deficiency caused widespread changes in their expression pattern, with a significant increase in the expression of PPAR␥, a master transcriptional regulator of lipid metabolism. However, the mRNA expression of the genes encoding the sphingosine kinases and S1P phosphatases, which directly control the levels of S1P, were not significantly changed in liver of the S1P lyase-deficient mice. These results demonstrate that S1P lyase is a key regulator of the levels of multiple sphingolipid substrates and reveal functional links between the sphingolipid metabolic pathway and other lipid metabolic pathways that may be mediated by shared lipid substrates and changes in gene expression programs. The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases.Sphingolipid metabolism generates diverse lipid molecules that are utilized by cells in multiple ways (Fig. 1A) (1, 2). Complex sphingolipids, such as sphingomyelin and glycosphingolipids, are structural components of cell membranes and drive the formation of plasma membrane lipid domains by virtue of their interactions with sterols. Metabolic intermediates, notably sphingosine, ceramide, and sphingosine-1-phosphate (S1P), 3 serve as bioactive molecules by regulating cellular signaling pathways. An additional function of sphingolipid metabolism is the synthesis of substrates that are utilized by other lipid metabolic hubs. However, the functional, regulatory, and physiological significance of the intersection of sphingolipid metabolism with other lipid pathways is not well understood.A decisive step in the sphingolipid metabolic pathway is carried out by S1P lyase, encoded by the Sgpl1 gene (3, 4). S1P lyase, which resides in the endoplasmic reticulum and is widely distributed in tissues, catalyzes the final degradative step in the sphingolipid metabolic pathway with the cleavage of phosphorylated sphingoid bases to generate phosphoethanolamine and a fatty aldehyd...

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Section: Discussionmentioning

confidence: 85%

Sphingosine 1-Phosphate Lyase Deficiency Disrupts Lipid Homeostasis in Liver

Bektas

Allende

Lee

et al. 2010

Journal of Biological Chemistry

181

198

View full text Add to dashboard Cite

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“…Indeed, it has been shown that genetic loss of acid sphingomyelinase can prevent diet-induced obesity, hyperglycaemia and insulin resistance in mice lacking the LDL receptor (Ldlr −/− ), which are prone to metabolic disease when placed on highfat diets [82]. Furthermore, a recent study by Bioni et al demonstrated that treatment of mice with the acidic sphingomyelinase inhibitor amitriptyline attenuates highfat diet-induced elevations in plasma ceramide and improves insulin sensitivity [78].…”

Section: Influence Of Caveolae In Mediating the Effects Of Ceramidementioning

confidence: 99%

Sphingolipids: agents provocateurs in the pathogenesis of insulin resistance

Lipina

Hundal

2011

Diabetologia

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Obesity is a major risk factor for a variety of chronic diseases, including diabetes mellitus, and comorbidities such as cardiovascular disorders. Despite recommended alterations in lifestyle, including physical activity and energy restriction, being the foundation of any antiobesity therapy, this approach has so far proved to be of little success in tackling this major public health concern. Because of this, alternative means of tackling this problem are currently being investigated, including pharmacotherapeutic intervention. Consequently, much attention has been directed towards elucidating the molecular mechanisms underlying the development of insulin resistance. This review discusses some of these potential mechanisms, with particular focus on the involvement of the sphingolipid ceramide. Various factors associated with obesity, such as saturated fatty acids and inflammatory cytokines, promote the synthesis of ceramide and other intermediates. Furthermore, studies performed in cultured cells and in vivo associate these sphingolipids with impaired insulin action. In light of this, we provide an account of the research investigating how pharmacological inhibition or genetic manipulation of enzymes involved in regulating sphingolipid synthesis can attenuate the insulin-desensitising effects of these obesity-related factors. By doing so, we outline potential therapeutic targets that may prove useful in the treatment of metabolic disorders.

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“…The mechanism by which this occurs is apparently not through an enhancement in lipogenesis and de novo triglyceride synthesis coupled to insulin resistance and hyperglycemia as is often reported in mice fed high fat diets (34,35). Instead, the current data indicate that the presence of cholesteryl ester is able to limit the mobilization of triglycerides from the liver, perhaps through the relative substrate flexibility previously reported in some neutral lipid-esterifying enzymes (32,33), such that the presence of CE interferes with TG hydrolysis and mobilization from cytoplasmic lipid droplets independent of lipogenesis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Acyl-Coenzyme A:Cholesterol Acyltransferase 2 (ACAT2) Prevents Dietary Cholesterol-associated Steatosis by Enhancing Hepatic Triglyceride Mobilization

Alger

Brown

Sawyer

et al. 2010

Journal of Biological Chemistry

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). All mouse models of diminished ACAT2 function showed lowered hepatic triglyceride concentrations and higher plasma triglycerides secondary to increased hepatic secretion of TG into nascent very low density lipoproteins. This work demonstrates that inhibition of hepatic ACAT2 can prevent dietary cholesterol-driven hepatic steatosis in mice. These data provide the first evidence to suggest that ACAT2-specific inhibitors may hold unexpected therapeutic potential to treat both atherosclerosis and non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease (NAFLD)4 is characterized by neutral lipid (triglyceride and cholesteryl ester (TG and CE)) accumulation in hepatocytes of patients with no history of chronic alcohol use (1, 2). Lipid droplets consisting of neutral lipids (triglyceride and cholesteryl ester) accumulate within the hepatocyte and can contribute 5-10% or more of the total mass of the liver (3). The causes of the lipid accumulation are not always clear, although a popular hypothesis is that excess free fatty acid availability to the liver in situations where energy excess prevails can lead to the condition (4). NAFLD is often asymptomatic and not regularly detected until progression into diseased fibrotic and/or inflamed non-alcoholic steatohepatitis and cirrhosis has occurred (5, 6). NAFLD is estimated to affect at least 20 and 5% of the general adult and child populations, respectively; it affects greater than 50% of the obese population in both age groups (3, 7). It is expected that as the prevalence of obesity and metabolic syndrome increases, NAFLD-associated diseases will be an increasing healthcare concern (8). Currently, there are no known effective treatments for NAFLD, although it is suggested that major changes in diet and exercise programs to reduce obesity could also diminish the severity and progression of NAFLD into non-alcoholic steatohepatitis and cirrhosis (2, 3, 5-9).The major tissue cholesterol-esterifying enzyme, acyl-CoA: cholesterol O-acyl transferase 2 (ACAT2 also known as SOAT2, sterol O-acyltransferase) is found within lipoproteinproducing cells such as intestinal enterocytes and hepatocytes (10, 11). It has been previously documented that ACAT2 plays a critical role in the production of atherogenic apoB-containing lipoproteins (12) and that ACAT2-specific inhibitors are extremely effective in preventing murine atherosclerosis (13). In addition to direct alterations in cholesterol metabolism, mice lacking ACAT2 exhibit unexpected hypertriglyceridemia, indicating that either increased production or decreased clearance of VLDL TG is altered in these mice (15). Despite this, ACAT2 deletion is highly atheroprotective (14), and it is reasonable to assume that much of the atheroprotective benefit of limiting ACAT2 can be explained by the diminished packaging of hepatic CE into atherogenic VLDL particles.Data from the present studies have uncovered an unexpected role for ACAT2 in hepatic TG metabolism. We have found that inhibition of ACAT2 not only has the expected outc...

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Acid Sphingomyelinase Deficiency Prevents Diet-induced Hepatic Triacylglycerol Accumulation and Hyperglycemia in Mice

Cited by 83 publications

References 35 publications

Sphingosine 1-Phosphate Lyase Deficiency Disrupts Lipid Homeostasis in Liver

Sphingosine 1-Phosphate Lyase Deficiency Disrupts Lipid Homeostasis in Liver

Sphingolipids: agents provocateurs in the pathogenesis of insulin resistance

Inhibition of Acyl-Coenzyme A:Cholesterol Acyltransferase 2 (ACAT2) Prevents Dietary Cholesterol-associated Steatosis by Enhancing Hepatic Triglyceride Mobilization

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