Abstract
Triglycerides can accumulate in injured tissues, a process thought to represent flux of excess, cytotoxic, free fatty acids into nontoxic triglyceride storage pools. However, this view may be overly simplistic, given that multiple pathways may impact triglyceride levels. This study sought new insights into this issue. Cultured human proximal tubule [human kidney-2 (HK-2)] cells or in vivo kidney were subjected to injuries known to increase triglyceride levels approximately three- to fourfold [HK-2 cells antimycin A-induced mitochondrial blockade; in vivo glycerol-induced rhabdomyolysis; endotoxemia). Six reverse transcription-polymerase chain reactions (RT-PCRs) were used to monitor mouse/human mRNAs for renal fatty acid transport protein (FATP2), or triglyceride-synthesizing enzymes (acyl-coenzyme A:diacylglycerol acyltransferases DGAT1 and DGAT2). Fatty acid synthase (FAS) and FATP2 were gauged by Western blot. FAS, FATP2, mitochondrial respiration, and phospholipase A2 (PLA(2)) effects on cell triglyceride accumulation were probed. Finally, tissue lipase activity was assessed. Antimycin A up-regulated multiple determinants of HK-2 cell triglyceride formation, including FATP2, FAS, DGAT1, and DGAT2 (proteins and/or mRNAs). However, neither FAS- nor FATP2-inhibition eliminated antimycin A-induced triglyceride loading, indicating the latter's multifactorial basis. PLA(2) activity increased FFA and triglyceride content. Rhabdomyolysis and endotoxemia altered multiple triglyceride homeostatic mechanisms. However, these changes were model-dependent and did not closely parallel those in HK-2 cells. Lipase activity signficantly fell (glycerol) or rose (endotoxemia) with different forms of tissue damage. Injury-induced triglyceride accumulation stems from multiple, and disease-specific, changes in triglyceride synthetic and degradative pathways. Simple flux of excess FFAs into triglyceride pools is an overly simplistic view of the post-injury-triglyceride loading state.
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