In vivo triglyceride synthesis in subcutaneous adipose tissue of humans correlates with plasma HDL parameters

Backgrounds and aims: Low concentrations of plasma HDL-C are associated with the development of atherosclerotic cardiovascular diseases and type 2 diabetes. Here we aimed to explore the relationship between the in vivo fractional synthesis of triglycerides (fTG) in subcutaneous (s.q.) abdominal adipose tissue (AT), HDL-C concentrations and HDL particle size composition in non-diabetic humans. Methods: The fTG in s.q. abdominal AT was measured in 16 non-diabetic volunteers (7 women, 9 men; Age: 49 ± 20 years; BMI: 31 ± 5 kg/m; Fasting Plasma Glucose: 90 ± 10 mg/dl) after 2H2O labeling. HDL-C concentration and subclasses, large (L-HDL), intermediate (I-HDL) and small (S-HDL) were measured. Results: Linear regression analyses demonstrated significant associations of fTG with plasma concentration of HDL-C (r = 0.625,p = 0.009) and percent contribution of L-HDL (r = 0.798,p < 0.001), I-HDL (r = -0.765,p < 0.001) and S-HDL (r = -0.629, p = 0.009). When analyses were performed by gender, the associations remained significant in women (HDL-C: r = 0.822,p = 0.023; L-HDL: r = 0.892,p = 0.007; I-HDL: r = -0.927,p = 0.003) but not men. Conclusions: Our study demonstrated an in vivo association between subcutaneous abdominal adipose tissue lipid dynamics and HDL parameters in humans, but this was true for women not men. Positive association with L-HDL and negative with I-HDL suggest that subcutaneous abdominal adipose tissue lipid dynamics may play an important role in production of mature functional HDL particles. Further studies evaluating the mechanism responsible for these associations and the observed gender differences are important and warranted to identify potential novel targets of intervention to increase the production of atheroprotective subclasses of HDL-Cs and thus decreasing the risks of development of atherosclerotic conditions

New technologies – new insights into the pathogenesis of hepatic encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome which frequently accompanies acute or chronic liver disease. It is characterized by a variety of symptoms of different severity such as cognitive deficits and impaired motor functions. Currently, HE is seen as a consequence of a low grade cerebral oedema associated with the formation of cerebral oxidative stress and deranged cerebral oscillatory networks. However, the pathogenesis of HE is still incompletely understood as liver dysfunction triggers exceptionally complex metabolic derangements in the body which need to be investigated by appropriate technologies. This review summarizes technological approaches presented at the ISHEN conference 2014 in London which may help to gain new insights into the pathogenesis of HE. Dynamic in vivo 13C nuclear magnetic resonance spectroscopy was performed to analyse effects of chronic liver failure in rats on brain energy metabolism. By using a genomics approach, microRNA expression changes were identified in plasma of animals with acute liver failure which may be involved in interorgan interactions and which may serve as organ-specific biomarkers for tissue damage during acute liver failure. Genomics were also applied to analyse glutaminase gene polymorphisms in patients with liver cirrhosis indicating that haplotype-dependent glutaminase activity is an important pathogenic factor in HE. Metabonomics represents a promising approach to better understand HE, by capturing the systems level metabolic changes associated with disease in individuals, and enabling monitoring of metabolic phenotypes in real time, over a time course and in response to treatment, to better inform clinical decision making. Targeted fluxomics allow the determination of metabolic reaction rates thereby discriminating metabolite level changes in HE in terms of production, consumption and clearance

The Molecular Basis for Load-Induced Skeletal Muscle Hypertrophy

In a mature (weight neutral) animal, an increase in muscle mass only occurs when the muscle is loaded sufficiently to cause an increase in myofibrillar protein balance. A tight relationship between muscle hypertrophy, acute increases in protein balance, and the activity of the mechanistic target of rapamycin complex 1 (mTORC1) was demonstrated 15 years ago. Since then, our understanding of the signals that regulate load-induced hypertrophy has evolved considerably. For example, we now know that mechanical load activates mTORC1 in the same way as growth factors, by moving TSC2 (a primary inhibitor of mTORC1) away from its target (the mTORC activator) Rheb. However, the kinase that phosphorylates and moves TSC2 is different in the two processes. Similarly, we have learned that a distinct pathway exists whereby amino acids activate mTORC1 by moving it to Rheb. While mTORC1 remains at the forefront of load-induced hypertrophy, the importance of other pathways that regulate muscle mass are becoming clearer. Myostatin, is best known for its control of developmental muscle size. However, new mechanisms to explain how loading regulates this process are suggesting that it could play an important role in hypertrophic muscle growth as well. Lastly, new mechanisms are highlighted for how β2 receptor agonists could be involved in load-induced muscle growth and why these agents are being developed as non-exercise-based therapies for muscle atrophy. Overall, the results highlight how studying the mechanism of load-induced skeletal muscle mass is leading the development of pharmaceutical interventions to promote muscle growth in those unwilling or unable to perform resistance exercise