Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes

Abstract

The pathogenesis of nonalcoholic steatohepatitis (NASH) is unclear, despite epidemiological data implicating FFAs. We studied the pathogenesis of NASH using lipoapoptosis models. Palmitic acid (PA) induced classical apoptosis of hepatocytes. PA-induced lipoapoptosis was inhibited by acyl-CoA synthetase inhibitor but not by ceramide synthesis inhibitors, suggesting that conversion products other than ceramide are involved. Phospholipase A 2 (PLA 2 ) inhibitors blocked PA-induced hepatocyte death, suggesting an important role for PLA 2 and its product lysophosphatidylcholine (LPC). Small interfering RNA for Ca 21 -independent phospholipase A 2 (iPLA 2 ) inhibited the lipoapoptosis of hepatocytes. PA increased LPC content, which was reversed by iPLA 2 inhibitors. Pertussis toxin or dominant-negative Ga i mutant inhibited hepatocyte death by PA or LPC acting through G-protein-coupled receptor (GPCR)/Ga i . PA decreased cardiolipin content and induced mitochondrial potential loss and cytochrome c translocation. Oleic acid inhibited PA-induced hepatocyte death by diverting PA to triglyceride and decreasing LPC content, suggesting that FFAs lead to steatosis or lipoapoptosis according to the abundance of saturated/unsaturated FFAs. LPC administration induced hepatitis in vivo. LPC content was increased in the liver specimens from NASH patients. These results demonstrate that LPC is a death effector in the lipoapoptosis of hepatocytes and suggest potential therapeutic values of PLA 2 inhibitors or GPCR/ Ga i inhibitors in

Serum Cytokeratin 18 M30 Antigen Level and Its Correlation with Nutritional Parameters in Middle-Aged Japanese Males with Nonalcoholic Fatty Liver Disease (NAFLD)

“…In our previous reports (28-30), we observed an elevation of serum LPC and an elevated SFA molar ratio of LPC in ovarian cancer, multiple myeloma and hemodialysis patients. LPC content was also increased in the liver specimens from NASH patients (26). An increase in LPC and SFA-LPC moieties may be another reason for the increase of SFA in plasma phospholipids of the present NAFLD group.…”

“…Prolonged SFA consumption induced glucose-dependent insulinotropic polypeptide elevation associated with adipokine imbalance and enhanced hepatocyte apoptosis (23). It has been demonstrated that SFAs are potentially cytotoxic in hepatocytes through their triggering of lipoapoptosis (24)(25)(26). A higher 16:0/18:2n-6 ratio observed in plasma phospholipids of the NAFLD group is an indicator of de novo lipogenesis (27).…”

Autophagy deficiency in beta cells leads to compromised unfolded protein response and progression from obesity to diabetes in mice

“…Islets were placed on Millicell culture plate inserts (Millipore, Carrigtwohill, Ireland) and treated with thapsigargin (Tg; Sigma, St Louis, MO, USA), palmitic acid (PA; Sigma) or oleic acid (OA; Sigma) as described [16]. To measure cell death, we determined oligonucleosomes released into the culture supernatant fraction by ELISA using a commercial kit (Roche, Mannheim, Germany) according to the manufacturer's instructions.…”

“…cDNA was synthesised using Superscript II (Invitrogen) and oligo(dT) [12][13][14][15][16][17][18] primer. Expression of UPR-related genes, antioxidant genes and p85α and p85β subunits of phosphoinositide 3-kinase (PI3K) was examined by real-time RT-PCR analysis using specific primers (electronic supplementary material [ESM] Table 1) [13].…”

Phylogenesis, Etiology and Pathogenesis of Insulin Resistance. Differences From Type Ii Diabetes Mellitus

“…Действие СРБ функционально связано с активностью фосфоли-пазы А 2 , которая после секреции ее в кровь также связы-вается с ЛПОНП [35]. Когда toll-рецепторы РСТ опре-деляют «замусоривание» межклеточной среды, действуя по принципу «свой -не свой» [36], фосфолипаза А 2 гидролизует фосфатидилхолин в ЛПОНП [37] и обра-зует лизофосфатидилхолин, с которым и связывается СРБ-пентамер. В физиологичных условиях СРБ в крови всегда ассоциирован с ЛПОНП.…”