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

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 diet-induced 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 diet-induced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.

Patient motion compensation during transthoracic 3-D echocardiography.

Bulk patient motion during transthoracic 3-D echocardiography (3DE) produces image plane misregistration and errors in left ventricular (LV) volume and ejection fraction (EF). To correct for patient motion, we used a magnetic locating system to track both the ultrasound transducer and the chest wall of the patient, so images could be registered in a patient-centered coordinate system ("correction"). Fourteen subjects each underwent 3DE, with deliberate patient motion, to measure LV volume and EF. Results were compared to magnetic resonance imaging (MRI). Without correction, 3DE differed significantly from MRI (EF: r = 0.78, SEE = 5.8%). Application of correction increased 3DE accuracy, despite patient motion (EF: r = 0.91, SEE = 3.7%), to a level comparable to that of 3DE in the absence of motion (EF: r = 0.93, SEE = 3.5%). Patient motion during 3DE examination can be corrected using a magnetic spatial location system.

Accuracy of three-dimensional echocardiography with unrestricted selection of imaging planes for measurement of left ventricular volumes and ejection fraction.

BACKGROUND: Accurate, reproducible, noninvasive determination of left ventricular (LV) volumes and ejection fraction (EF) is important for clinical assessment, risk stratification, selection of therapy, and serial monitoring of patients with cardiovascular disease. Three-dimensional echocardiography (3DE) approaches have demonstrated significantly greater accuracy than current clinical 2DE, but the clinical utility of 3DE has been limited because of the need for substantial modifications to scanning technique (eg, all image acquisition from a single acoustic window) or cumbersome additional hardware. We describe a novel 3DE system without these limitations and its application to patients. METHODS AND RESULTS: Twenty-five patients were examined by 3DE, 2DE, and magnetic resonance imaging (MRI). The 3DE system used a magnetic scanhead tracking device, and volumes were computed with a novel deformable shell model. End-diastolic volumes and EF by MRI ranged from 96 to 375 mL and 18% to 73%, respectively. There was excellent correlation, without statistically significant differences, between MRI and 3DE for end-systolic volume (ESV) (r(2) = 0.99) and end-diastolic volume (EDV) (r(2) = 0.98), ventricular stroke volume (SV) (r(2) = 0.93), and EF (r(2) = 0.97), with standard error estimates less than 10 mL for volumes and 3% for EF. Conventional 2DE consistently underestimated volumes (EDV, P <.01; ESV, P <.01; SV, P <.05); correlations with MRI were r(2) = 0.91 for ESV, r(2) = 0.88 for EDV, r(2) = 0.62 for SV, and r(2) = 0.72 for EF. Standard error estimates ranged from 16 to 20 mL for ventricular volumes and 9% for EF. Interobserver variability was reduced 3-fold with use of 3DE. CONCLUSIONS: The novel 3DE system allows unrestricted selection and combination of acoustic windows in a single examination, improves accuracy of estimates of LV volumes and EF 3-fold compared with 2DE, and is practical for routine clinical assessment of LV size and function in patients with a wide range of cardiac pathology.