Team Rachel Fisher

Working model of hepatic triglyceride (TG) metabolism (LD: lipid-droplet)

Research focus

Investigation of disturbed lipid metabolism in liver and adipose tissue as contributors to cardiometabolic disease

Introduction

The overarching objective of the Fisher team is to use translational approaches to elucidate pathways in human liver and adipose tissue that, when disturbed, contribute to the development of cardiometabolic disease, in particular cardiovascular disease and type 2 Diabetes Mellitus. Research in the team follows two main lines.

Functional characterization of novel proteins involved in hepatic triglyceride metabolism

Disturbances in hepatic triglyceride (TG) metabolism are central in the dysregulation of plasma TG concentrations and the development of hepatic steatosis, conditions that increase risk for cardiovascular disease, severe liver disease, insulin resistance and Diabetes Mellitus. Therapeutic options to treat these conditions are extremely limited, largely as a consequence of an incomplete understanding of the physiology of TG-metabolism in human liver. In our laboratory we evaluate the role of candidate proteins in hepatic TG-metabolism and have identified, amongst others, TM6SF2 as a regulator of liver fat metabolism influencing the secretion of TG-rich lipoproteins and hepatic lipid-droplet metabolism.

While the TG-hydrolase PNPLA2 has been reported to play an important role in the mobilization of TG from hepatic lipid-droplets in mouse liver cells, the function of this enzyme in human hepatic TG-metabolism has thus far not been evaluated. Using protocols developed in our laboratory to study key aspects of TG-metabolism in human liver cell-lines, we have evaluated the role of PNPLA2 and its activator ABHD5 in the secretion of TG-rich lipoproteins and hepatic lipid-droplet metabolism. Surprisingly, we found that PNPLA2 and ABHD5 selectively influence the hepatic secretion of TG-rich lipoproteins without influencing the mobilization of TGs from mature lipid-droplets. Moreover, confocal microscopy studies indicate that PNPLA2 is not associated with large lipid-droplets, but with structures that probably represent small lipid-droplets associated with the endoplasmic reticulum. On the basis of these studies we propose that PNPLA2 is a critical component of the TG-rich lipoprotein synthesis pathway (as outlined in the figure above). Since our candidate-gene approach has so far failed to identify the TG-hydrolase(s) associated with mature lipid-droplets in human liver we aim to develop a more efficient system to screen candidate proteins from the metabolic serine-hydrolase protein-family for roles in hepatic TG-metabolism.

Participants

Ferdinand M van ‘t Hooft MD, PhD, Senior Researcher

Characterisation of adipose tissue dysfunction as a cardiometabolic risk factor

While an inflammatory state is a well-recognised risk factor for cardiovascular disease, low grade systemic inflammation and insulin resistance also occur together with adipose tissue being a site of inflammation. In adipose tissue of obese and insulin resistant subjects the number of pro-inflammatory macrophages and the production of inflammatory cytokines is increased, while adiponectin production is decreased. Inflammation within adipose tissue has been shown to promote the development of atherosclerosis in mouse models and to be associated with cardiovascular risk factors in humans. Why macrophages are recruited into adipose tissue is unknown, although a key role for the chemokine CCL2 (monocyte chemoattractant protein 1, MCP-1) and has been demonstrated. Adipocyte hypertrophy, adipocyte death and local hypoxia have all been proposed as stimuli for macrophage infiltration, but the underlying mechanisms remain unclear.

Research within the team focuses on determining how local ceramide production in human adipose tissue is related to macrophage accumulation, inflammation adipose tissue metabolism, since our data have implicated ceramides in these processes. Additionally, we are interested in differences between adipose tissue located at different sites within the body in terms of inflammation, ceramide metabolism and relationships to cardimetabolic risk factors. By studying different human adipose tissue depots (subcutaneous, intra-thoracic, intra-abdominal and perivascular) we are able to consider the consequences of adipose tissue dysfunction on the development of cardiometabolic disease at both the local and systemic levels. We use a range of techniques to achieve these goals, combining molecular genetic, human metabolic and epidemiological approaches. Furthermore, adipose tissue from a range of patient groups is studied.

Participants

Olivera Werngren Laboratory Assistant

Networks and collaborations

The team is located in a centre for translational cardio-metabolic research at the Centre for Molecular Medicine with extensive expertise in bioinformatics and translational research. The team is affiliated to the Strategic Research Programme in Diabetes at Karolinska Institutet. We participate in the hepatic TG-metabolism Consortium in collaboration with Robert Farese and Tobias Walther (Harvard, Boston), Sekar Kathiresan (Broad, Boston) USA and Vivek Malhotra (Barcelona), to identify and functionally characterise novel genes/proteins involved in the regulation of the secretion of TG-rich lipoproteins.

Team members

Rachel Fisher PhD, Professor, Team Leader

Ferdinand M van ‘t Hooft MD, PhD, Senior Researcher

Louisa Cheung PhD, Research Assistant Professor (FoAss)

Olivera Werngren Laboratory Assistant

Recent key publications

Altered Protein Composition of Subcutaneous Adipose Tissue in Chronic Kidney Disease.
Gertow J, Ng CZ, Mamede Branca RM, Werngren O, Du L, Kjellqvist S, et al
Kidney Int Rep 2017 Nov;2(6):1208-1218

TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.
Mahdessian H, Taxiarchis A, Popov S, Silveira A, Franco-Cereceda A, Hamsten A, et al
Proc. Natl. Acad. Sci. U.S.A. 2014 Jun;111(24):8913-8

DGAT1 participates in the effect of HNF4A on hepatic secretion of triglyceride-rich lipoproteins.
Krapivner S, Iglesias MJ, Silveira A, Tegnér J, Björkegren J, Hamsten A, et al
Arterioscler. Thromb. Vasc. Biol. 2010 May;30(5):962-7

Insulin-induced gene 2 involvement in human adipocyte metabolism and body weight regulation.
Krapivner S, Popov S, Chernogubova E, Hellénius ML, Fisher RM, Hamsten A, et al
J. Clin. Endocrinol. Metab. 2008 May;93(5):1995-2001

Psoriasis Skin Inflammation-Induced microRNA-26b Targets NCEH1 in Underlying Subcutaneous Adipose Tissue.
Cheung L, Fisher RM, Kuzmina N, Li D, Li X, Werngren O, et al
J. Invest. Dermatol. 2016 Mar;136(3):640-648

Ceramides are associated with inflammatory processes in human mediastinal adipose tissue.
Gertow J, Kjellqvist S, Ståhlman M, Cheung L, Gottfries J, Werngren O, et al
Nutr Metab Cardiovasc Dis 2014 Feb;24(2):124-31

Human mediastinal adipose tissue displays certain characteristics of brown fat.
Cheung L, Gertow J, Werngren O, Folkersen L, Petrovic N, Nedergaard J, et al
Nutr Diabetes 2013 May;3():e66

Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue.
Kolak M, Gertow J, Westerbacka J, Summers SA, Liska J, Franco-Cereceda A, et al
Lipids Health Dis 2012 Sep;11():115

Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts.
Kotronen A, Yki-Järvinen H, Aminoff A, Bergholm R, Pietiläinen KH, Westerbacka J, et al
Eur. J. Endocrinol. 2009 Apr;160(4):593-602

Fatty acid desaturases in human adipose tissue: relationships between gene expression, desaturation indexes and insulin resistance.
Sjögren P, Sierra-Johnson J, Gertow K, Rosell M, Vessby B, de Faire U, et al
Diabetologia 2008 Feb;51(2):328-35

ApoB/apoA-I ratio: an independent predictor of insulin resistance in US non-diabetic subjects.
Sierra-Johnson J, Romero-Corral A, Somers VK, Lopez-Jimenez F, Walldius G, Hamsten A, et al
Eur. Heart J. 2007 Nov;28(21):2637-43