Stearoyl-CoA Desaturase 1 (SCD1) is a key factor mediating diabetes in MyD88-deficient mice

Yokoyama, Shota; Hosoi, Toru; Ozawa, Koichiro

doi:10.1016/j.gene.2012.01.024

Cited by 17 publications

(18 citation statements)

References 27 publications

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“…This also partially explains the quantity of conflicting data existing when investigating whole-body Myd88 deletion and its impact of obesity and related disorders. [15][16][17] We showed that LKO mice had a normal glucose tolerance on CT diet. However, in this dietary condition, LKO mice already exhibited significantly lower hepatic glycogen content and a higher insulin secretion after oral glucose stimulation.…”

Section: Discussionmentioning

confidence: 97%

“…13 14 In another context, the deletion of MyD88 has been shown to increase the risk of developing type 2 diabetes and hepatic steatosis under HFD feeding. [15][16][17] Altogether, evidence strongly supports a role of MyD88 signalling in hepatic disturbances associated with obesity; however, the convergent molecular mechanisms and target tissues remain to be clarified.…”

Section: Significance Of This Studymentioning

confidence: 99%

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Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

Duparc

Plovier

Marrachelli

et al. 2016

Gut

133

112

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ObjectiveTo examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism.DesignTo study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH).ResultsHepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis.ConclusionsOur study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans.

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Section: Discussionmentioning

confidence: 97%

Section: Significance Of This Studymentioning

confidence: 99%

Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

Duparc

Plovier

Marrachelli

et al. 2016

Gut

133

112

View full text Add to dashboard Cite

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“…Some mutations of this enzyme have been linked to alterations in intracellular lipid metabolism and development of obesity, metabolic syndrome, and T2D, suggesting a potential role as actor in glucose control. In support of this hypothesis, it has been demonstrated that stearoyl-CoA desaturase-deficient mice have increased energy expenditure, reduced body visceral fat masses, decreased insulin resistance, and they are not prone to high fat diet-induced obesity and liver steatosis [59].…”

Section: Dyslipidemia Contributing To Diabetes and Vascular Complicatmentioning

confidence: 91%

Dyslipidemia and Diabetes: Reciprocal Impact of Impaired Lipid Metabolism and Beta-Cell Dysfunction on Micro- and Macrovascular Complications

Rotella²,

2012

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■ AbstractPatients with diabetes frequently exhibit the combined occurrence of hyperglycemia and dyslipidemia. Published data on their coexistence are often controversial. Some studies provide evidence for suboptimal lifestyle and exogenous hyperinsulinism at "mild insulin resistance" in adult diabetic patients as main pathogenic factors. In contrast, other studies confirm that visceral adiposity and insulin resistance are the basic features of dyslipidemia in type 2 diabetes (T2D). The consequence is an excess of free fatty acids, which causes hepatic gluconeogenesis to increase, metabolism in muscles to shift from glucose to lipid, beta-cell lipotoxicity, and an appearance of the classical "lipid triad", without real hypercholesterolemia. Recently, it has been proposed that cholesterol homeostasis is important for an adequate insulin secretory performance of beta-cells. The accumulation of cholesterol in beta-cells, caused by defective high-density lipoprotein (HDL) cholesterol with reduced cholesterol efflux, induces hyperglycemia, impaired insulin secretion, and beta-cell apoptosis. Data from animal models and humans, including humans with Tangier disease, who are characterized by very low HDL cholesterol levels, are frequently associated with hyperglycemia and T2D. Thus, there is a reciprocal influence of dyslipidemia on beta-cell function and inversely of beta-cell dysfunction on lipid metabolism and micro-and macrovascular complications. It remains to be clarified how these different but mutually influencing adverse effects act in together to define measures for a more effective prevention and treatment of micro-and macrovascular complications in diabetes patients. While the control of circulating low-density lipoprotein (LDL) cholesterol and the level of HDL cholesterol are determinant targets for the reduction of cardiovascular risk, based on recent data, these targets should also be considered for the prevention of betacell dysfunction and the development of type 2 diabetes. In this review, we analyze consolidated data and recent advances on the relationship between lipid metabolism and diabetes mellitus, with particular attention to the reciprocal effects of the two features of the disease and the development of vascular complications.

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“…The ∆9 desaturase steroyl-CoA desaturase 1 (SCD1) is important for the generation of monounsaturated fatty acids during lipogenesis. It plays a role in inflammatory regulation, and its upregulation is correlated to many metabolic diseases including obesity and insulin resistance [18,19]. Previous studies indicate that dietary protein composition plays an important role in the regulation of fatty acid desaturation as well as cholesterol metabolism [14,20,21].…”

Section: Introductionmentioning

confidence: 99%

A fish protein hydrolysate alters fatty acid composition in liver and adipose tissue and increases plasma carnitine levels in a mouse model of chronic inflammation

et al. 2013

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BackgroundThere is growing evidence that fish protein hydrolysate (FPH) diets affect mitochondrial fatty acid metabolism in animals. The aim of the study was to determine if FPH could influence fatty acid metabolism and inflammation in transgene mice expressing human tumor necrosis factor alpha (hTNFα).MethodshTNFα mice (C57BL/6 hTNFα) were given a high-fat (23%, w/w) diet containing 20% casein (control group) or 15% FPH and 5% casein (FPH group) for two weeks. After an overnight fast, blood, adipose tissue, and liver samples were collected. Gene expression and enzyme activity was analysed in liver, fatty acid composition was analyzed in liver and ovarian white adipose tissue, and inflammatory parameters, carnitine, and acylcarnitines were analyzed in plasma.ResultsThe n-3/n-6 fatty acid ratio was higher in mice fed the FPH diet than in mice fed the control diet in both adipose tissue and liver, and the FPH diet affected the gene expression of ∆6 and ∆9 desaturases. Mice fed this diet also demonstrated lower hepatic activity of fatty acid synthase. Concomitantly, a lower plasma INF-γ level was observed. Plasma carnitine and the carnitine precursor γ-butyrobetaine was higher in the FPH-group compared to control, as was plasma short-chained and medium-chained acylcarnitine esters. The higher level of plasma acetylcarnitine may reflect a stimulated mitochondrial and peroxisomal β-oxidation of fatty acids, as the hepatic activities of peroxisomal acyl-CoA oxidase 1 and mitochondrial carnitine palmitoyltransferase-II were higher in the FPH-fed mice.ConclusionsThe FPH diet was shown to influence hepatic fatty acid metabolism and fatty acid composition. This indicates that effects on fatty acid metabolism are important for the bioactivity of protein hydrolysates of marine origin.

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Stearoyl-CoA Desaturase 1 (SCD1) is a key factor mediating diabetes in MyD88-deficient mice

Cited by 17 publications

References 27 publications

Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

Dyslipidemia and Diabetes: Reciprocal Impact of Impaired Lipid Metabolism and Beta-Cell Dysfunction on Micro- and Macrovascular Complications

A fish protein hydrolysate alters fatty acid composition in liver and adipose tissue and increases plasma carnitine levels in a mouse model of chronic inflammation

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