Activation of Peroxisome Proliferator–Activated Receptor Alpha Enhances Apoptosis in the Mouse Liver

Abstract

Chronic exposure to peroxisome proliferators (PPs) leads to increased incidence of liver tumors in rodents. Liver tumor induction is thought to require increased hepatocyte proliferation and suppression of apoptosis. Transcript profiling showed increased expression of proapoptotic genes and decreased expression of antiapoptotic genes in the livers of mice exposed to the PP WY-14,643 (WY). We tested the hypothesis that prior exposure to WY would increase susceptibility to apoptosis inducers such as Jo2, an antibody which activates the Fas (Apo-1/CD95) death pathway. When compared to their untreated counterparts, wild-type mice pretreated with WY exhibited increased caspase-3 activation and hepatocyte apoptosis following challenge with Jo2. Livers from WY-treated peroxisome proliferator-activated receptor alpha (PPARalpha)-null mice were resistant to the effects of Jo2. In the absence of Jo2 and detectable apoptosis, wild-type mice treated with WY exhibited increases in the activated form of caspase-9. As caspase-9 is a component of the apoptosome, we examined the expression of upstream effectors of apoptosome activity including members of the Bcl-2 family. The levels of the antiapoptotic Mcl-1 transcript and protein were significantly decreased by PPs. PPARalpha-null mice were also resistant to another treatment (concanavalin A) that induces hepatocyte apoptosis. These results (1) indicate that PPARalpha activation increases sensitivity of the liver to apoptosis and (2) identify a mechanism by which PPARalpha could serve as a pharmacological target in diseases where apoptosis is a contributing feature.

Clofibrate treatment in pigs: Effects on parameters critical with respect to peroxisome proliferator-induced hepatocarcinogenesis in rodents

“…This suggestion agrees with recent studies which have shown that clofibrate induces apoptosis in human and rat hepatoma cells [55-59]. In agreement with our study, a recent study showed that treatment with WY 14,643 up-regulates pro-apoptotic genes and down regulates anti-apoptotic genes in the liver of mice, an effect which did not occur in PPARα-null mice [60]. In that study, it was also demonstrated that PPARα activation increases the sensitivity of liver towards apoptosis by Jo-2, an inducer of hepatic apoptosis.…”

Cytotoxic Properties of Clofibrate and other Peroxisome Proliferators: Relevance to Cancer Progression

“…A recent study shows that in clofibrate-treated pigs the expression of the pro-apoptotic protein Bax is up-regulated, while the levels of the antiapoptotic factor Bcl-x L are reduced, which may provide the basis for an increase of apoptotic cell death. In agreement with this report, treatment of mice with Wy-14,643 has been shown to upregulate the expression of pro-apoptotic genes and to down regulate that of anti-apoptotic factors in the liver, while PPARα-null mice appear protected against these modifications [98]. The same study shows that PPARα activation by Wy-14643 also increases liver sensitivity to apoptosis induced by treatment with agonist anti-Fas antibodies.…”

“…Finally, PPAR-dependent signal transduction pathway may be effectively modulated in the future by means of siRNA or antisense methodologies, or by selective PPAR modulators, able to exert most of the benefits, while reducing the adverse effects displayed by full PPAR agonists [136]. Wy-14,643 hepatocytes [98] perfluoroctanoic acid liver cancer cells [5] Nafenopin liver cancer cells [3] BR931 liver cancer cells [6] conjugated linoleic acid liver cancer cells [138] TDZ18 lymphocytic leukemia [139] MCC-555 colon cancer cells [140] PPAR/ GW0742 colon cancer cells [141] PPAR TDZ (troglitazone, rosiglitazone, ciglitazone, pioglitazone, TDZ18, MCC-555) osteoblasts, promyelocytic leukaemia, lymphocytic leukaemia, colon, breast, liver, thyroid, ovarian, and lung cancer [7,8,139,140,[142][143][144] 15d-PGJ2 neurons, B-lymphocytes, Blymphoma,promyelocytic leukaemia, colon, breast, thyroid and lung cancer (142,143,(145)(146)(147) DEHP Sertoli cells [148] DHEP = Di(2-ethylhexyl) phthalate; TDZ = thiazolidindione;…”

“…By contrast, in human HepG2 hepatoblastoma cells, clofibrate-induced apoptosis is associated with increased PPAR levels [115]. Another study reported that PPAR activation enhances hepatocyte apoptosis [98]. By contrast, in FAO hepatoma cells PPAR has been shown to be required for the protection against nafenopininduced death [120].…”

Different Mechanisms of DEHP‐induced Hepatocellular Adenoma Tumorigenesis in Wild‐type and Pparα‐null Mice

“…Mcl1, a member of the Bcl-2 family, strongly inhibits tBid-induced cytochrome c release 31) , and delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells 32) and hematopoietic cells 33) . Short-term treatment of mice with Wy-14,643 significantly decreased the levels of anti-apoptotic Mcl1 transcript and protein in wild-type mice, but not in Pparα-null mice 34) , suggesting the involvement of PPARα in Mcl1 expression. Since the dose of DEHP used in this experiment was relatively low and activated PPARα very weakly, the effect on Mcl1 might not have been observable in the wild-type mice.…”