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By Jamshed Arslan, Pharm. D., PhD.
Insulin resistance in adipocytes is a major feature of metabolic syndrome . Disrupted adipose tissue metabolism can lead to accumulation of lipid intermediates in insulin-sensitive tissues like liver and skeletal muscles, thereby diminishing insulin sensitivity. A key enzyme in adipocytes that mobilizes free fatty acids from adipose tissue into the bloodstream is hormone-sensitive lipase (HSL). Deficiency of this lipolytic enzyme has shown improvements in whole-body insulin sensitivity in obese mice, but the pathway linking hormone-sensitive lipase to insulin signaling is not well understood. Working on this puzzle, researchers from European and Canadian institutes genetically manipulated mouse and human adipocytes and found that hormone-sensitive lipase physically interacts with and blocks Carbohydrate-response element-binding protein (ChREBP), a carbohydrate-signaling transcription factor. The nuclear translocation of ChREBP is known to induce a lipogenic enzyme ELOVL6. So, it was not surprising to note that inhibiting hormone-sensitive lipase in adipocytes augmented the production of ELOVL6 and improved insulin sensitivity. In short, hormone-sensitive lipase is linked to insulin signaling through ChREBP and its target ELOVL6.
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To understand the effect of ablating hormone-sensitive lipase on glucose metabolism, the team silenced the hormone-sensitive lipase gene in human adipocytes and tracked radiolabeled glucose under basal and insulin-stimulated conditions. The siRNA-induced silencing of hormone-sensitive lipase enhanced insulin-stimulated transport and oxidation of glucose as well as de novo lipogenesis (DNL). Hormone-sensitive lipase depletion also enhanced the proportion of oleic acid but decreased that of palmitic and palmitoleic acids. This motivated scientists to analyze the genes responsible for glucose-derived fatty acid synthesis. Out of many DNL genes, they found a robust increase in fatty acid elongase ELOVL6. In other words, hormone-sensitive lipase depletion modified fat composition by inducing ELOVL6.
To observe the effect of ELOVL6 on insulin sensitivity, the team knocked down ELOVL6 in human adipocytes and mice, and analyzed its impact on the beneficial effects of hormone-sensitive lipase depletion such as insulin-mediated phosphorylation of IRS1 and AKT. The results showed that the effects of hormone-sensitive lipase reduction, including insulin sensitivity and oleic acid synthesis, were dependent on ELOVL6. The next step was to find the factors/pathways linking hormone-sensitive lipase to ELOVL6.
When visceral adipocytes become insulin resistant, disinhibition of hormone-sensitive lipase leads to palmitate/FFA efflux into the portal circulation, leading to hepatic uptake, hepatic insulin resistance, and fatty liver. Diagram from Metabolic Syndrome Signaling Poster , published in its original form in a collaborative between Dr. Robert H. Lustig, Dr. Alejandro Gugliucci and Bio-Techne Corporation
This study shows that hormone-sensitive lipase deficiency releases nuclear factor ChREBP into the nucleus, leading to insulin sensitivity and synthesis of oleic acid, which is also a key component of olive oil. Based on this research, lead molecules targeting the hormone-sensitive lipase -ChREBP interaction could be developed against metabolic syndrome, and particularly to alleviate type 2 diabetes.
Jamshed Arslan, Pharm D, PhD
Dr. Arslan is an Assistant Professor at Dow University of Health Sciences, Pakistan,
where he teaches Pharmacology to future pharmacists.
Research in focus
Morigny, P., Houssier, M., Mairal, A., Ghilain, C., Mouisel, E., Benhamed, F., … Langin, D. (2019). Interaction between hormone-sensitive lipase and ChREBP in fat cells controls insulin sensitivity. Nature Metabolism. https://doi.org/10.1038/s42255-018-0007-6
