Hepatic steatosis results from several processes. To assess their relative roles, hepatocellular long chain fatty acid (LCFA) uptake was assayed in hepatocytes from C57BL/6J control mice (C), mice with steatosis from a high fat diet (HFD) or 10, 14, or 18% ethanol (EtOH) in drinking water (functioning leptin signaling groups, FLSGs), and ob/ob and db/db mice. Uptake Vmax was increased vs C (p<0.001) and correlated significantly with liver weight and triglycerides in all FLSGs, but was minimally or not increased in ob/ob and db/db, in which liver weights & triglycerides greatly exceeded projections from regressions in FLSGs. Coefficients of determination (R2) for these FLSG regressions suggest that increased LCFA uptake accounts for ~80% of the increase in hepatic triglycerides within these groups, but increased lipogenic gene expression data suggest that enhanced LCFA synthesis is the major contributor in ob/ob and db/db. Got2, Cd36, Slc27a2, and Slc27a5 gene expression ratios were significantly up-regulated in the EtOH groups, correlating with both SREBP1c and Vmax, but only Cd36 expression was increased in HFD, ob/ob, and db/db. Comparison of Vmax with serum insulin and leptin suggests that both hormones contribute to up-regulation of uptake in FLSG mice. Thus, increased LCFA uptake, reflecting SREBP1c-mediated up-regulation of 4 distinct transporters, is the dominant cause of steatosis in EtOH-fed mice. In ob/ob and db/db mice, increased LCFA synthesis appears more important. In FLSG animals insulin up-regulates hepatocellular LCFA uptake. Leptin appears either to up-regulate LCFA uptake or to be essential for full expression of up-regulation by insulin.
- fatty acid transport
- fatty acid synthesis
- Copyright © 2009, American Journal of Physiology- Gastrointestinal and Liver Physiology