Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance

Gutiérrez‐Juárez, Roger; Pocai, Alessandro; Mulas, Claudia; Ono, Hiraku; Bhanot, Sanjay; Monia, Brett P.; Rossetti, Luciano

doi:10.1172/jci26991

Cited by 275 publications

(185 citation statements)

References 53 publications

Supporting

Mentioning

167

Contrasting

Unclassified

Order By: Relevance

“…There is strong evidence that downregulation of SCD1 prevents or reduces the development of NAFLD, obesity and insulin resistance [29][30][31][32]. Elevated hepatic transcription of Scd1 has been reported in fat-fed mice of the 129S6 [13] and C57BL/6J [13,23] strains.…”

Section: Discussionmentioning

confidence: 99%

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

et al. 2007

View full text Add to dashboard Cite

Aims/hypothesis Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with dietinduced NAFLD. Materials and Methods Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks. Glucose tolerance, in vivo insulin secretion, plasma lipid profile and adiposity were determined. Plasma metabonomics and liver transcriptomics were used to identify changes in gene expression associated with HFD-induced NAFLD.Results In HFD-fed mice, NAFLD and impaired glucose and lipid homeostasis were associated with increased hepatic transcription of genes involved in fatty acid uptake, intracellular transport, modification and elongation, whilst genes involved in beta-oxidation and lipoprotein secretion were, paradoxically, also upregulated. NAFLD developed despite strong and sustained downregulation of transcription of the gene encoding stearoyl-coenzyme A desaturase 1 (Scd1) and uncoordinated regulation of transcription of Scd1 and the gene encoding sterol regulatory element binding factor 1c (Srebf1c) transcription. Inflammatory mechanisms appeared to be stimulated by HFD. Conclusions/interpretation Our results provide an accurate representation of subtle changes in metabolic and gene expression regulation underlying disease-promoting and compensatory mechanisms, collectively contributing to dietinduced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

et al. 2007

View full text Add to dashboard Cite

show abstract

Section: The Impact Of Liver Scd1 Deficiency On Obesity and Insulin Rmentioning

confidence: 99%

“…Using the hyperinsulinemic-euglycemic clamp method, ASOmediated inhibition of SCD1 was shown to prevent short-term (5-day) high-fat diet-induced hepatic insulin resistance in mice and rats, without affecting whole-body glucose uptake [83]. These effects were observed using both intraperitoneal ASO injection, which affects both liver and adipose, as well as intraportal ASO infusion, which is liver specific [83]. Short-term ASO-mediated SCD1 inhibition also caused enhanced hepatic insulin signaling, suppression of hepatic gluconeogenic gene expression (Pepck and G6pase) and accumulation of hepatic triglycerides [83].…”

Section: The Impact Of Liver Scd1 Deficiency On Obesity and Insulin Rmentioning

confidence: 99%

“…These effects were observed using both intraperitoneal ASO injection, which affects both liver and adipose, as well as intraportal ASO infusion, which is liver specific [83]. Short-term ASO-mediated SCD1 inhibition also caused enhanced hepatic insulin signaling, suppression of hepatic gluconeogenic gene expression (Pepck and G6pase) and accumulation of hepatic triglycerides [83]. These effects, however, were not observed in liver-specific LKO mice generated by the Cre-lox system [42 •• ].…”

Section: The Impact Of Liver Scd1 Deficiency On Obesity and Insulin Rmentioning

confidence: 99%

See 1 more Smart Citation

Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism

Flowers

Ntambi

2008

Current Opinion in Lipidology

369

308

View full text Add to dashboard Cite

Purpose of review-Stearoyl-coenzyme A desaturase 1 is a δ-9 fatty acid desaturase that catalyzes the synthesis of monounsaturated fatty acids and has emerged as a key regulator of metabolism. This review evaluates the latest advances in our understanding of the pivotal role of stearoyl-coenzyme A desaturase 1 in health and disease.Recent findings-scd1-deficient mice have reduced lipid synthesis and enhanced lipid oxidation, thermogenesis and insulin sensitivity in various tissues including liver, muscle and adipose tissue due to transcriptional and posttranscriptional effects. These metabolic changes protect scd1-deficient mice from a variety of dietary, pharmacological and genetic conditions that promote obesity, insulin resistance and hepatic steatosis. Stearoylcoenzyme A desaturase 1 is required to guard against dietary unsaturated fat deficiency, leptin deficiency-induced diabetes, and palmitate-induced lipotoxic insults in muscle and pancreatic β-cells. Paradoxical observations of increased muscle stearoyl-coenzyme A desaturase 1 during obesity, starvation and exercise raise questions as to the role of stearoyl-coenzyme A desaturase 1 in this tissue. Mice with a liverspecific loss of stearoyl-coenzyme A desaturase 1, and inhibition of stearoyl-coenzyme A desaturase 1 via antisense or RNA interference, recapitulate only a subset of the phenotypes observed in global Scd1 deficiency, indicating the involvement of multiple tissues.Summary-Recent studies in humans and animal models have highlighted that modulation of stearoyl-coenzyme A desaturase 1 activity by dietary intervention or genetic manipulation strongly influences several facets of energy metabolism to affect susceptibility to obesity, insulin resistance, diabetes and hyperlipidemia.

show abstract

“…Third, the knockout (KO) of Acc2 (also known as Acacb) resulted in increased energy expenditure as measured by the volume of oxygen consumed Á V O 2 [7,8]. It has also been shown that inhibition of the downstream genes Scd1 and Dgat2 also lowers Acc1 (also known as Acaca) and Acc2 expression by a feedback mechanism [9][10][11]. These results supported drug research targeted approaches to lower malonyl-CoA.…”

Section: The Premisementioning

confidence: 72%

Targeting energy expenditure via fuel switching and beyond

Geisler

2010

Diabetologia

View full text Add to dashboard Cite

Since over-nutrition accelerates the development of obesity, progression to type 2 diabetes, and the associated co-morbidity and mortality, there has been a keen interest in therapeutic interventions targeting mechanisms that may curb appetite, increase energy expenditure or at least attenuate insulin resistance. Over the past decade, numerous peri-mitochondrial targets in the de novo lipid synthesis pathway have been linked to an increase in energy expenditure and the drug development industry has pursued the gene products involved as candidates to develop drugs against. The basis of this link, and specifically the premise that lowering tissue and cellular malonyl-CoA can increase energy expenditure, is scrutinised here. The argument presented is that fuel switching as effected by changes in cellular malonyl-CoA concentrations will not trigger the mitochondria to increase energy expenditure because: (1) an increase in beta-oxidation by lowering respiratory exchange ratio (indicative of the metabolic fuel consumed) does not equal an increase in energy expenditure (how rapidly fuel is consumed); (2) the ATP:oxygen ratios (i.e. ATP energy made:oxygen required for the reaction) are similar when metabolising lipids (2.8) vs glucose (3.0); (3) substrate availability (NEFA) does not drive energy expenditure in vivo; and (4) the availability of ADP in the mitochondrial matrix determines the rate of energy expenditure, not the availability of fuel to enter the mitochondrial matrix. To increase mitochondrial energy expenditure, work must be done (exercise) and/or the mitochondrial proton leak must be enhanced, both of which increase availability of ADP. In fact, despite the historic taboo of chemical uncoupling, this mechanism validated in humans is closest on task to increasing whole-body energy expenditure. Chemical uncoupling mimics the naturally occurring phenomenon of proton leak, accelerating the metabolism of glucose and lipids. However, it is completely non-genomic (i.e. the target is a location, not a gene product) and is not associated with addiction or mood alterations common to satiety agents. A significant hurdle for drug development is to discover a safe mitochondrial uncoupler and to formulate it potentially as a pro-drug and/or oral pump, to avoid the issue of overdosing experienced in the 1930s. The potential therapeutic impact of such a compound for an overnutritioned patient population could be profound. If effective, the mitochondrial uncoupler mechanism could resolve many of the associated diseases such as type 2 diabetes, hypertension, obesity, depression, sleep apnoea, non-alcoholic steatohepatitis, insulin resistance and hyperlipidaemia, therefore becoming a 'disease-modifying therapy'.

show abstract

Critical role of stearoyl-CoA desaturase-1 (SCD1) in the onset of diet-induced hepatic insulin resistance

Cited by 275 publications

References 53 publications

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism

Targeting energy expenditure via fuel switching and beyond

Contact Info

Product

Resources

About