Background & Aims p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD). Methods C75Bl/6J mice were fed a high-fat (HFD) or control diet for 8 weeks, PFT or DMSO (vehicle) were administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western-blot, real-time PCR and biochemical assays. Results PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PFT. Thus, induction of these two pathways by PFT diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation and decreased steatosis. Additionally, we also demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid- treated human HepaRG cells. Conclusions The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD by depleting mCoA and favoring the β-oxidation of fatty acids.

Chronic ethanol consumption in the Long-Evans (LE) rat has been associated with hepatic p53 activation, and inhibition of the insulin/PI3K/AKT signal transduction cascade due to increased expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN). We hypothesize that p53 activation and altered insulin signaling may influence the susceptibility of rats to ethanol-induced liver damage. Furthermore, p53 not only activates programmed cell death pathways and suppresses hepatocellular survival signals, but promotes gluconeogenesis to increase systemic insulin resistance due to a novel metabolic function. Here, we present evidence that chronic ethanol feeding in Fischer (F), Sprague-Dawley (SD) and LE rats promotes p53 activation, hepatic steatosis, oxidative stress, p53 up-regulated modulator of apoptosis (PUMA) and PTEN expression, which contribute to hepatocellular death and diminished insulin signaling in the liver. Such changes are pronounced in the LE, less prominent in SD, and virtually absent in the F rat strain. More importantly, there is activation of Tp53-induced glycolysis and apoptosis regulator (TIGAR) in the ethanol-fed LE rat. This event generates low hepatic fructose-2, 6-bisphosphate (Fru-2,6-P 2 ) levels, reduced lactate/pyruvate ratio and may contribute to increased basal glucose turnover and high residual hepatic glucose production during euglycemic hyperinsulinemic clamp. Conclusions: p53 activation correlates with the susceptibility to ethanol-induced liver damage in different rat strains. p53 not only orchestrates apoptosis and suppresses cell survival, but by activating TIGAR and decreasing hepatic Fru-2,6-P 2 levels it may also promote insulin resistance and therefore, contribute to the metabolic abnormalities associated with hepatic steatosis.

Introduction Wire localization (WL) of non-palpable breast cancers on the day of surgery is uncomfortable for patients and impacts OR efficiency. Radioactive seed localization (RSL) before the day of surgery avoids these disadvantages. In this study we compare outcomes of our initial 6-month experience with RSL to those with WL in the preceding 6 months. Methods Lumpectomies for invasive or intraductal cancers localized with a single 125iodine seed (January-June 2012) were compared to those using 1 wire (July-December 2011). Surgeons and radiologists did not change. Positive and close margins were defined as tumor on ink and tumor ≤1mm from ink, respectively. Demographic and clinical characteristics and outcomes were compared between RSL and WL patients. Results There were 431 RSL and 256 WL lumpectomies performed. Clinicopathologic characteristics did not differ between groups. Most seeds (90%) were placed before the day of surgery. Positive margins were present in 7.7% of RSL versus 5.5% of WL patients, and 16.9% of RSL versus 19.9% of WL had close margins (p=0.38). The median operative time was longer for lumpectomy and sentinel lymph node biopsy (SLNB) in the RSL group (55 versus 48 minutes, p<0.0001). There was no significant difference in the volume of tissue excised between groups. Conclusions In the first 6 months of RSL, operative scheduling was simplified, while rates of positive and close margins were similar to those seen after many years of experience with WL. Operative time was slightly longer for RSL lumpectomy and SLNB; we anticipate this will decrease with experience.