Background-Stearoyl-coenzyme A desaturase 1 (SCD1) is a well-known enhancer of the metabolic syndrome. The purpose of the present study was to investigate the role of SCD1 in lipoprotein metabolism and atherosclerosis progression. Methods and Results-Antisense oligonucleotides were used to inhibit SCD1 in a mouse model of hyperlipidemia and atherosclerosis (LDLr Ϫ/Ϫ Apob 100/100 ). In agreement with previous reports, inhibition of SCD1 protected against diet-induced obesity, insulin resistance, and hepatic steatosis. Unexpectedly, however, SCD1 inhibition strongly promoted aortic atherosclerosis, which could not be reversed by dietary oleate. Further analyses revealed that SCD1 inhibition promoted accumulation of saturated fatty acids in plasma and tissues and reduced plasma triglyceride, yet had little impact on low-density lipoprotein cholesterol. Because dietary saturated fatty acids have been shown to promote inflammation through toll-like receptor 4, we examined macrophage toll-like receptor 4 function. Interestingly, SCD1 inhibition resulted in alterations in macrophage membrane lipid composition and marked hypersensitivity to toll-like receptor 4 agonists. Conclusions-This study demonstrates that atherosclerosis can occur independently of obesity and insulin resistance and argues against SCD1 inhibition as a safe therapeutic target for the metabolic syndrome.

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Key points Prenatal alcohol exposure has the potential to affect fetal development and programme chronic disease in offspring. Previous preclinical models typically use high, chronic doses of alcohol throughout pregnancy to examine effects on offspring, particularly on the brain and behaviour. In this study we use a rat model of moderate, acute, prenatal alcohol exposure to determine if this can be detrimental to maintenance of glucose homeostasis in adolescent and adult offspring. Although female offspring were relatively unaffected, there was evidence of insulin resistance in 6‐month‐old male offspring exposed to prenatal alcohol, suggestive of a pre‐diabetic state. This result suggests that even a relatively low‐dose, acute exposure to alcohol during pregnancy can still programme metabolic dysfunction in a sex‐specific manner. Abstract Alcohol consumption is highly prevalent amongst women of reproductive age. Given that approximately 50% of pregnancies are unplanned, alcohol has the potential to affect fetal development and programme chronic disease in offspring. We examined the effect of an acute but moderate prenatal alcohol exposure (PAE) on glucose metabolism, lipid levels and dietary preference in adolescent and/or adult rat offspring. Pregnant Sprague–Dawley rats received an oral gavage of ethanol (1 g kg−1 maternal body weight, n = 9 dams) or an equivalent volume of saline (control, n = 8 dams) at embryonic days 13.5 and 14.5. PAE resulted in a blood alcohol concentration of 0.05–0.06% 1 h post‐gavage in dams. Fasting blood glucose concentration was not affected by PAE in offspring at any age, nor were blood glucose levels during a glucose tolerance test (GTT) in 6‐month‐old offspring (P > 0.5). However, there was evidence of insulin resistance in PAE male offspring at 6 months of age, with significantly elevated fasting plasma insulin (P = 0.001), a tendency for increased first phase insulin secretion during the GTT and impaired glucose clearance following an insulin challenge (P = 0.007). This was accompanied by modest alterations in protein kinase B (AKT) signalling in adipose tissue. PAE also resulted in reduced calorie consumption by offspring compared to controls (P = 0.04). These data suggest that a relatively low‐level, acute PAE programmes metabolic dysfunction in offspring in a sex‐specific manner. These results highlight that alcohol consumption during pregnancy has the potential to affect the long‐term health of offspring.

Background-Stearoyl-CoA desaturase 1 (SCD1) is a critical regulator of energy metabolism and inflammation. We have previously reported that inhibition of SCD1 in hyperlipidemic mice fed a saturated fatty acid (SFA)-enriched diet prevented development of the metabolic syndrome, yet surprisingly promoted severe atherosclerosis. In this study we tested whether dietary fish oil supplementation could prevent the accelerated atherosclerosis caused by SCD1 inhibition. Methods and Results-LDLr, ApoB 100/100 mice were fed diets enriched in saturated fat or fish oil in conjunction with antisense oligonucleotide (ASO) treatment to inhibit SCD1. As previously reported, in SFA-fed mice, SCD1 inhibition dramatically protected against development of the metabolic syndrome, yet promoted atherosclerosis. In contrast, in mice fed fish oil, SCD1 inhibition did not result in augmented macrophage inflammatory response or severe atherosclerosis. In fact, the combined therapy of dietary fish oil and SCD1 ASO treatment effectively prevented both the metabolic syndrome and atherosclerosis. Conclusions-SCD1

BackgroundHepatic macrosteatosis (HMS) is prevalent among high BMI patients, but a lack of validation of non-invasive measures of liver fat hampers non-alcoholic liver disease (NAFLD) investigation in general. Recent work suggests BMI adjusted, non-contrasted computed tomography (nc-CT) attenuation data (Hounsfield units) reflects liver fat accumulation in a normal weight population. However, this and other CT-based HMS studies have only approximated macrosteatosis (%) histologically, but have not validated findings with chemical liver triglyceride (TG) concentrations (mg/gram protein). Also, all previous CT based steatosis studies excluded high BMI subjects, whose habitus may affect properties of the scan. We hypothesized that in high BMI patients nc-CT attenuation measurements expressed in Hounsfield units (HU) accurately estimate liver triglyceride concentrations as well as histological macrosteatosis.MethodsWith informed consent, 15 patients underwent nc-CT scan of the abdomen prior to weight loss surgery with intraoperative wedge and core needle liver biopsy. Mean left lobe nc-CT Hounsfield units (CTL), liver TG (mg/g Pr), HMS (%), BMI (kg/m2), liver-spleen index (CTL/S = hepatic HU/splenic HU), and liver–spleen difference (CTL-S = hepatic HU − splenic HU) were a priori outcomes.ResultsIn 15 patients (11 female) with a BMI of 44.4 ± 1.1 (mean ± SEM), CTL/S, CTL-S, and CTL measures were significantly associated with liver TG concentrations (r = −0.80, P < 0.001; r = −0.80, P < 0.001; and r = −0.71, P < 0.01, respectively; Table 1). Macrosteatosis (%) and liver triglyceride concentration were positively associated (r = 0.83; P < 0.0001). BMI did not correlate strongly to liver triglyceride (r = 0.44, P = NS).ConclusionEstimates of liver fat obtained by nc- CT scans (esp. CTL/S, CTL-S) correlate to chemical measurement of liver triglyceride concentrations, suggesting non-contrasted CT may be a suitable non-invasive “gold standard” for hepatic steatosis quantification in these patients.