L-Fabp expression decreased 10-fold following HSC activation, concomitant with depletion of LDs. Primary HSCs isolated from L-FABP−/− mice contain fewer LDs than wild-type (WT) HSCs, and exhibit up-regulated expression of genes involved in HSC activation. Adenoviral L-Fabp transduction inhibited activation of passaged WT HSCs and increased both the expression

of prolipogenic genes and also augmented intracellular lipid accumulation, including triglyceride and FA, predominantly palmitate. Freshly isolated HSCs from L-FABP−/− mice correspondingly exhibited decreased palmitate in the free FA pool. To investigate whether L-FABP deletion promotes Selleck HIF inhibitor HSC activation in vivo, we fed L-FABP−/− and WT mice a high-fat diet supplemented with trans-fatty acids and fructose (TFF). TFF-fed L-FABP−/− mice exhibited reduced hepatic steatosis along with decreased LD abundance and size compared to WT mice. In addition, TFF-fed L-FABP−/− mice exhibited decreased hepatic fibrosis, with reduced expression of fibrogenic genes, compared to WT mice. Conclusion: L-FABP deletion

attenuates both diet-induced hepatic steatosis and fibrogenesis, despite the observation that L-Fabp paradoxically promotes FA and LD accumulation and inhibits HSC activation in vitro. These findings highlight the importance of cell-specific modulation of hepatic lipid metabolism in promoting fibrogenesis in nonalcoholic fatty liver disease. (Hepatology 2013) Nonalcoholic fatty liver disease (NAFLD) encompasses a selleck compound 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 Protein kinase N1 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 (FAs).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).