Liver fatty acid binding protein (L-Fabp) modulates murine stellate cell activation and diet-induced nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathology ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis (1). Neutral lipid storage in hepatocytes, principally in the form of triglyceride, predisposes individuals to the subsequent development and progression of NASH (2) although much is still poorly understood regarding the metabolic regulation and clinical significance of distinctive storage pools of intrahepatic lipid. Among these intracellular storage compartments, lipid droplets (LDs) have emerged as a focal point of interest (3). LDs are specialized spherical organelles composed of a core of neutral lipids surrounded by proteins known as perilipins (Plins), which play key roles in regulating aspects of intracellular trafficking, signaling and cytoskeletal organization (4). Understanding the pathways that regulate metabolic flux in LDs is likely to provide insight into the mechanisms of lipid-mediated liver injury (5). Hepatic stellate cells (HSCs) are the major effectors of hepatic fibrogenesis, characterized in their quiescent state by abundant LDs containing predominantly retinyl esters, triglyceride and cholesterol ester along with cholesterol, phospholipids, and fatty acids (FA) (6, 7). In the course of hepatic injury, quiescent HSCs undergo phenotypic changes including enhanced cell proliferation, loss of LDs, expression of α-smooth muscle actin (α-SMA), and excessive production of extracellular matrix (ECM). HSC activation is coupled with a reduction in lipogenesis and diminished expression of prolipogenic transcription factors, (8, 9), which together reflect an ‘anti-adipogenic’ program (10). However, the dynamic relationship between lipid metabolic pathways in hepatocytes and stellate cells is incompletely understood and the elements that regulate LD accumulation upon HSC activation remain obscure (11). Mammalian intracellular fatty acid-binding proteins (FABPs) comprise a superfamily of lipid-binding proteins (12) involved in the uptake, transport and metabolism of FA and other lipid ligands. Liver Fabp (L-Fabp or Fabp1) is abundantly expressed in both hepatocytes and enterocytes and binds multiple ligands, including saturated FA and cholesterol (12). Germline L-Fabp−/− mice exhibit decreased hepatic triglyceride content (13) with altered FA uptake kinetics. In addition, L-Fabp−/− mice fed a high saturated fat, high cholesterol “Western” diet were protected against diet-induced obesity and hepatic steatosis, likely reflecting altered kinetics of saturated FA utilization (14, 15). Proteomic screens revealed L-Fabp to be overexpressed in obese subjects with simple steatosis, along with paradoxically decreased expression in the progressive versus mild forms of NASH (16). Recent studies have validated new models of diet-induced NAFLD with fibrosis in murine models (17, 18), setting the stage for formal exploration of the role of candidate genes in the progressive forms of murine NAFLD. Here we explore a role for L-Fabp in lipid metabolism in both hepatocytes and stellate cells and report the impact of L-Fabp deletion in diet-induced HSC activation and hepatic fibrosis in vivo.