. Essential fatty acid deficiency in mice is associated with hepatic steatosis and secretion of large VLDL particles. Am J Physiol Gastrointest Liver Physiol 288: G1150 -G1158, 2005. First published January 20, 2005 doi:10.1152/ajpgi.00456.2004.-Essential fatty acid (EFA) deficiency in mice decreases plasma triglyceride (TG) concentrations and increases hepatic TG content. We evaluated in vivo and in vitro whether decreased hepatic secretion of TG-rich very low-density lipoprotein (VLDL) contributes to this consequence of EFA deficiency. EFA deficiency was induced in mice by feeding an EFAdeficient (EFAD) diet for 8 wk. Hepatic VLDL secretion was quantified in fasted EFAD and EFA-sufficient (EFAS) mice using the Triton WR-1339 method. In cultured hepatocytes from EFAD and EFAS mice, VLDL secretion into medium was measured by quantifying [3 H]-labeled glycerol incorporation into TG and phospholipids. Hepatic expression of genes involved in VLDL synthesis and clearance was measured, as were plasma activities of lipolytic enzymes. TG secretion rates were quantitatively similar in EFAD and EFAS mice in vivo and in primary hepatocytes from EFAD and EFAS mice in vitro. However, EFA deficiency increased the size of secreted VLDL particles, as determined by calculation of particle diameter, particle sizing by light scattering, and evaluation of the TG-to-apoB ratio. EFA deficiency did not inhibit hepatic lipase and lipoprotein lipase activities in plasma, but increased hepatic mRNA levels of apoAV and apoCII, both involved in control of lipolytic degradation of TG-rich lipoproteins. EFA deficiency does not affect hepatic TG secretion rate in mice, but increases the size of secreted VLDL particles. Present data suggest that hypotriglyceridemia during EFA deficiency is related to enhanced clearance of altered VLDL particles. hepatic lipoprotein secretion; lipoprotein clearance; hypotriglyceridemia DEVELOPMENT OF HEPATIC STEATOSIS is a well-established manifestation of essential fatty acid (EFA) deficiency in animal models. It was first described in 1958 in rats by Alfin-Slater and Bernick (3) and in 1970 by Fukazawa et al. (12) and Sinclair and Collins (43). The excess lipid deposited in the liver during EFA deficiency can theoretically result from increased uptake of circulating lipids, enhanced de novo lipogenesis, decreased fatty acid oxidation, or decreased hepatic lipoprotein secretion, or from a combination of these. Increased hepatic lipogenesis and decreased fatty acid oxidation could indeed contribute, because polyunsaturated fatty acids are physiological suppressors of fatty acid synthesis (4, 31) through downregulation of SREBP1c (16, 42, 51) and inducers of hepatic fatty acid oxidation through activation of PPAR␣, respectively. The quantitative contribution of increased lipogenesis and decreased oxidation to EFA deficiency-induced hepatic steatosis has not been established. Whereas the effects of EFA deficiency on induction of hepatic steatosis are fairly consistent in the literature, the consequences for he...