Triglyceride Mobilization from Lipid Droplets Sustains the Anti-Steatotic Action of Iodothyronines in Cultured Rat Hepatocytes.

Elena Grasselli,Fernando Goglia,Elena Silvestri,Giulia Vecchione,Andrea D. Compalati,Adriana Voci,Laura Vergani,Gabriella Gallo,Ilaria Demori,Rita De Matteis

doi:10.3389/fphys.2015.00418

Abstract

Adipose tissue, dietary lipids and de novo lipogenesis are sources of hepatic free fatty acids (FFAs) that are stored in lipid droplets (LDs) as triacylglycerols (TAGs). Destiny of TAGs stored in LDs is determined by LD proteomic equipment. When adipose triglyceride lipase (ATGL) localizes at LD surface the lipid mobilization is stimulated. In this work, an in vitro model of cultured rat hepatocytes mimicking a mild steatosis condition was used to investigate the direct lipid-lowering action of iodothyronines, by focusing, in particular, on LD-associated proteins, FFA oxidation and lipid secretion. Our results demonstrate that in “steatotic” hepatocytes iodothyronines reduced the lipid excess through the recruitment of ATGL on LD surface, and the modulation of the LD-associated proteins Rab18 and TIP47. As an effect of ATGL recruitment, iodothyronines stimulated the lipid mobilization from LDs then followed by the up-regulation of carnitine-palmitoyl-transferase (CPT1) expression and the stimulation of cytochrome-c oxidase (COX) activity that seems to indicate a stimulation of mitochondrial function. The lipid lowering action of iodothyronines did not depend on increased TAG secretion. On the basis of our data, ATGL could be indicated as an early mediator of the lipid-lowering action of iodothyronines able to channel hydrolyzed FFAs toward mitochondrial beta-oxidation rather than secretion.

Highlights

Hepatic lipid accumulation results from both an increased uptake of circulating free fatty acids (FFAs) rising from adipose tissue or dietary lipids, and/or de novo lipogenesis
Primary rat hepatocytes exposed for 24 h to a mixture of non-esterified fatty acids (NEFAs) mimic a mild steatosis condition that is reversed by treatment with T2, or T3, for 24 h
Cytosol was punctuated by small adipose triglyceride lipase (ATGL)-positive droplets (Figure 1E), in “steatotic” hepatocytes, fat accumulation was accompanied by a reduction in the number of small ATGLpositive droplets, with the appearance of numerous and large ATGL-negative droplets (Figure 1F)

Summary

Introduction

Hepatic lipid accumulation results from both an increased uptake of circulating free fatty acids (FFAs) rising from adipose tissue or dietary lipids, and/or de novo lipogenesis. Excess lipid accumulation leads to hepatic steatosis which is characterized by the accumulation of triacylglycerols (TAGs) in cytosolic lipid droplets (LDs) (Khor et al, 2013). LD accumulation maintains low intracellular level of free fatty acids (FFAs) to avoid their toxic effects on cellular physiology. LDs consist of a core of neutral lipids (mainly TAGs) that is bounded by a monolayer of phospholipids and LD coat proteins. LDs were considered passive fat depots, but they are recognized as dynamic organelles at the hub of lipid and energy metabolism (Thiam et al, 2013). The dynamicity of LDs is documented by changes in the expression of LD proteome

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Results

Conclusion