Hepatic Steatosis

Project 1:

Optimizing the beneficial health effects of exercise for diabetes: focus on the liver!

One of the earliest hallmarks of type 2 diabetes is resistance of the peripheral tissues liver and muscle to the action of insulin, which is generally referred to as insulin resistance. Physical exercise training is perhaps the single most effective intervention to both prevent and treat insulin resistance and type 2 diabetes mellitus. Moreover, exercise training often has beneficial health effects – such as improvements in cardiovascular risk markers – that extend beyond the improvements of insulin sensitivity. Accumulating evidence now suggests that the liver plays an important role in determining the overall health benefits of exercise training in healthy human subjects and type 2 diabetic patients, but the underlying mechanisms are unclear.

Using a multidisciplinary but strongly integrated approach, we will address whether the beneficial effects of exercise training on metabolic risk markers are determined by effects on liver metabolism, and we will investigate the underlying molecular pathways. We will investigate the effect of acute exercise and exercise training on liver fat content and liver mitochondrial metabolism in diabetic patients (subproject 1) and extend these findings to relevant mouse models (subproject 2). In addition, we will identify proteins released from skeletal muscle into the circulation during acute exercise and following exercise training (myokines; subproject 3), and their expression will be correlated with liver fat and other metabolic parameters in diabetic patients. The physiological and molecular effects of these myokines on hepatic metabolism, fat storage, and function will be addressed in mouse models (subproject 2) and tissue culture systems (subproject 4). Finally, we will identify novel components of the skeletal muscle extracellular “metabolome” and test their effects on hepatic lipid metabolism (subprojects 2, 3 and 4). Together, these 4 subprojects are expected to provide better insight into how exercise programs can be optimized to treat the complications of type 2 diabetes mellitus. In addition, understanding the underlying molecular pathways may reveal novel targets for the treatment of the metabolic abnormalities associated with type 2 diabetes.

This project is financed by a grant from the Dutch Diabetes Research Foundation (DFN)
PhD-student: Bram Brouwers
Collaborators: Prof. Dr. Sander Kersten, Wageningen University
Prof. Dr. Eric Kalkhoven, Utrecht University

Project 2:

Hepatic steatosis: Imaging the fate of fat

Hepatic triglyceride accumulation (steatosis) is a major health threat, giving rise to insulin resistance and hyperlipidemia. At present >30% of adults suffer from fatty liver due to the increased obesity prevalence. New evidence suggests that low hepatic ATP concentrations -indicative of compromised mitochondrial function- may underlie triglyceride accumulation. Using novel non-invasive Magnetic Resonance Spectroscopy (MRS) tools we propose to test the hypothesis that diminished hepatic mitochondrial function (investigated by 31P-MRS) leads to excessive retention of dietary fat in the liver, ultimately resulting in hepatic steatosis. Dietary fatty acid (FA) retention will be determined by 13C-MRSbased fatty FA-tracking and steatosis will be determined by 1H-MRS. We will combine human and rodent experiments to study physiological relevance and molecular mechanisms. Given the massive (and growing) number of patients with fatty liver and insulin resistance, the importance of efficient treatment and prevention is evident. Identifying hepatic mitochondrial function as a central player in the development of steatosis and insulin resistance can lead to new targets to prevent diabetes and other obesity-linked morbidity.

This project is financed by a VENI grant from the Netherlands Organisation for Scientific Research (NWO), granted to Dr. Vera Schrauwen-Hinderling

Project 3:

Liver fat, insulin sensitivity and diabetes/cardiovascular risk: roads towards prevention and treatment.

Worldwide prevalence of obesity has reached epidemic proportions and is still increasing. Excessive fat deposition in and around the organs, defined as ectopic fat, is associated with obesity. If excessive fat is stored in the liver, in absence of high alcohol consumption, this is diagnosed as non-alcoholic fatty liver (NAFL). Strikingly, the prevalence of NAFL in obese people may be as high as 50–70%. Moreover, ectopic fat accumulation in the liver is associated with impairments in metabolic health. Therefore, hepatic fat accumulation might be an interesting target for the prevention and treatment of metabolic diseases. Pathways involved in hepatic fat accumulation include several routes of fat storage and mobilization: dietary fat retention after a meal, de novo lipogenesis, hepatic uptake of non-esterified fatty acids, export of VLDL (very low density lipoproteins), hepatic fat oxidation and disposal by ketogenesis. However, knowledge on the importance of the different pathways in causing NAFL is sparse, in part because of a lack in appropriate techniques. Therefore, one part of this project focuses on advances in MR spectroscopy techniques to study liver metabolism in humans. Subsequently, these MR-based techniques will be used to study the different pathways contributing to hepatic fat and how these relate to metabolic health (e.g. insulin resistance). Furthermore, it is of interest how modulation of diet composition may alter liver fat content, and ultimately metabolic health. Small-scale human studies will be performed and results will be combined with large-scale population-based longitudinal studies on the health impact of liver fat, performed at Leiden University Medical Center. All together, this project will improve our understanding of the determinants of liver fat and their consequences on metabolic health and will reveal whether liver fat should be considered a target for interventions aimed at improving metabolic health in humans.

This project is financed by a public-private partnership within TKI/Health Holland with Unilever Research Vlaardingen as industrial partner
Collaborators: Prof. Dr. Frits Rosendaal, Leiden University Medical Center and Unilever Research Vlaardingen
PhD Students: Kay Roumans, Pandichelvam Veeraiah