The prototypic extracellular phospholipid mediator, lysophosphatidic acid (LPA), exhibits growth factor-like properties and represents an important survival factor in serum. This potent mesangial cell mitogen is increased in conditions associated with glomerular injury and is a known activator of the classic MAPK pathway, which plays an important role in the regulation of mesangial cell hexokinase (HK) activity. To better understand the mechanisms coupling metabolism to injury, we examined the ability of LPA to regulate HK activity and expression in cultured murine mesangial cells. LPA increased total HK activity in both a concentration- and time-dependent manner, with maximal increases of >50% observed within 12 h of exposure to LPA at concentrations 25 µM (apparent ED₅₀ 2 µM). These effects were associated with increased ERK activity and were prevented by the pharmacologic inhibition of either MEK or PKC. Increased HK activity was also associated with increased glucose (Glc) utilization and lactate accumulation, as well as selectively increased HKII isoform abundance. The ability of exogenous LPA to increase HK activity was both Ca²⁺-independent and PTX-insensitive and was mimicked by LPA-generating phospholipase A₂. We conclude that LPA constitutes a novel lipid regulator of mesangial cell HK activity and Glc metabolism. This regulation requires sequential activation of both Ca²⁺-independent PKC (nPKC) and the classic MAPK pathway and culminates in increased HKII abundance. These previously unrecognized metabolic consequences of LPA stimulation have both physiologic and pathophysiologic implications. They also suggest a novel mechanism whereby metabolism may be coupled to cellular injury via extracellular lipid mediators.