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Keynote Lecturer Professor Marja-Riitta Taskinen on hepatic and lipoprotein metabolism

Tuesday 8 May 2018   (0 Comments)
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Disturbances in hepatic and lipoprotein metabolism is the hallmark of atherogenic dyslipidaemia  - What can we learn to improve the management of atherogenic dyslipidaemia?

Professor Marja-Riitta Taskinen (Research Program Unit, Diabetes & Obesity Research program, University of Helsinki Finland) is a truly a pioneer in lipoprotein metabolism working at the interface of diabetes and lipid metabolism. Her contributions to this area of research have led to numerous awards, most recently the prestigious Robert Levy Memorial lecture at the 2017 American Heart Association Scientific Sessions.

Atherogenic dyslipidaemia, characterized by elevated triglycerides, accumulation of remnant particles, small dense low-density lipoprotein (LDL), low plasma concentration of high-density lipoprotein (HDL) cholesterol, and increases in apolipoprotein CIII (apoCIII) and aoB-100 is a major driver of cardiovascular risk in individuals who are obese and/or have type 2 diabetes. Importantly, atherogenic dyslipidaemia is also a feature of non-alcoholic fatty liver disease (NAFLD), which has been estimated to affect about one in four individuals world-wide, even higher in regions such as the Middle East and South America.1 However, this is likely to be an underestimate, given the escalating dual pandemics of obesity and type 2 diabetes.

The different components of atherogenic dyslipidaemia are not isolated abnormalities but closely linked to each other metabolically.  Elevated triglycerides are caused by dual lipid defects: increased secretion and impaired clearance of triglyceride-rich lipoproteins.2 Recent studies have also clarified the mechanisms underpinning the increase in apoCIII levels, largely as a consequence of an increase in the apoCIII secretion rate, but secondarily, due to an increase in the apoCIII fractional catabolic rate. Moreover, glycaemic control appears to be an important mediator of apoCIII dynamics in individuals with type 2 diabetes.3

How can we modulate triglyceride levels and postprandial lipaemia, key features of atherogenic dyslipidaemia in type 2 diabetes? First, carriage of APOC3 loss of function variants resulting in complete loss of apoCIII, has been shown to markedly lower both parameters,4 providing a clear rationale for the development of antisense oligonucleotide targeting apoCIII.

However, is it possible to adopt dietary approaches to resolve atherogenic dyslipidaemia, specifically by reducing dietary carbohydrate intake, as recommended for the management of non-alcoholic fatty liver disease (NAFLD)? According to a study reported by Professor Taskinen this is indeed feasible. In obese individuals with NAFLD, an isocaloric low carbohydrate diet (<30 g carbohydrate per day for 14 days) led to a rapid decrease in de novo lipogenesis and increase in beta-oxidation, which together contributed to rapid decreases in levels of very low-density-triglycerides and apoCIII, as well as decreases in lipid fat.  This dietary approach has other benefits, specifically changes in the gut microbiota flora, increasingly recognized as a key player in obesity and cardiometabolic disease.5 Given the rapidity of these changes – evident within a 2-week period – there is clear potential for investigating diet-microbiota interactions for the management of NAFLD.  

 

References

1. Younossi ZM, Koenig AB, Abdelatif D et al.  Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84.

2. Borén J, Watts GF, Adiels M et al. Kinetic and related determinants of plasma triglyceride concentration in abdominal obesity: multicenter tracer kinetic study. ATVB 2015;35:2218-24.

3. Taskinen MR, Borén J. Why Is apolipoprotein CIII emerging as a novel therapeutic target to reduce the burden of cardiovascular disease?  Curr Ather Reports 2016;18:1059.

4. Saleheen D, Natarajan P, Armean IM et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 2017;544:235-9.

5. Mardinoglu A, Wu H, Bjornson E et al. An integrated understanding of the rapid metabolic benefits of a carbohydrate-restricted diet on hepatic steatosis in humans. Cell Metab 2018;27:559-571.


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