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Nehra, Vandana; Angulo, Paul; Buchman, Alan L.; Lindor, Keith D.

doi:10.1023/a:1012338828418

Cited by 132 publications

(43 citation statements)

References 39 publications

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“…PUMA Is Up-regulated in Human NASH-Clinically, circulating FFA are elevated in the metabolic syndrome and in patients with NASH (15). PUMA expression was assessed in human liver specimens, comparing obese normal control liver specimens to those with simple steatosis and steatosis plus inflammation (NASH).…”

Section: Resultsmentioning

confidence: 99%

“…Elevated serum FFA levels and hepatocyte apoptosis are hallmarks of NASH, and levels of circulating FFA correlates with liver disease severity (14,15). Prior studies have identified structural and functional mitochondrial abnormalities (48,67,68) as well as an endoplasmic reticulum stress-induced JNK activation in liver cells from NASH patients (16).…”

Section: Discussionmentioning

confidence: 99%

“…FFAs were added to Dulbecco's modified Eagle's medium containing 1% bovine serum albumin to assure a physiologic ratio between bound and unbound FFA in the media, approximating the molar ratio present in plasma (47). The concentration of FFA used in the experiments (800 M) was similar to the fasting FFA plasma concentrations observed in human non-alcoholic steatohepatitis, ranging from 700 to 1000 M (15,48,49). The concentration of the vehicle, isopropyl alcohol, was 1% in final incubations.…”

Section: Methodsmentioning

confidence: 99%

“…Saturated and unsaturated FFA differ in regard to their potential for lipoapoptosis; saturated long-chain FFA are significantly more toxic than unsaturated FFA (12,13). Therefore, it is not surprising that NASH is characterized by both an elevation of serum FFA levels and hepatocyte apoptosis, and the magnitude of circulating FFA correlates with disease severity (14,15).…”

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confidence: 99%

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JNK1-dependent PUMA Expression Contributes to Hepatocyte Lipoapoptosis

Cazanave

Mott

Elmi

et al. 2009

Journal of Biological Chemistry

179

236

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Free fatty acids (FFA) induce hepatocyte lipoapoptosis by a c-Jun N-terminal kinase (JNK)-dependent mechanism. However, the cellular processes by which JNK engages the core apoptotic machinery during lipotoxicity, especially activation of BH3-only proteins, remain incompletely understood. Thus, our aim was to determine whether JNK mediates induction of BH3-only proteins during hepatocyte lipoapoptosis. The saturated FFA palmitate, but not the monounsaturated FFA oleate, induces an increase in PUMA mRNA and protein levels. Palmitate induction of PUMA was JNK1-dependent in primary murine hepatocytes. Palmitate-mediated PUMA expression was inhibited by a dominant negative c-Jun, and direct binding of a phosphorylated c-Jun containing the activator protein 1 complex to the PUMA promoter was identified by electrophoretic mobility shift assay and a chromatin immunoprecipitation assay. Short hairpin RNA-targeted knockdown of PUMA attenuated Bax activation, caspase 3/7 activity, and cell death. Similarly, the genetic deficiency of Puma rendered murine hepatocytes resistant to lipoapoptosis. PUMA expression was also increased in liver biopsy specimens from patients with non-alcoholic steatohepatitis as compared with patients with simple steatosis or controls. Collectively, the data implicate JNK1-dependent PUMA expression as a mechanism contributing to hepatocyte lipoapoptosis.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

JNK1-dependent PUMA Expression Contributes to Hepatocyte Lipoapoptosis

Cazanave

Mott

Elmi

et al. 2009

Journal of Biological Chemistry

179

236

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“…Current concepts indicate that FFA, and not their esterified product (triglyceride), mediate hepatic lipotoxicity (11,12). Elevated serum FFA correlate with liver disease severity (13)(14)(15), and therapies that enhance insulin sensitivity ameliorate hepatic lipotoxicity, in part, by decreasing plasma FFA (16). Hepatic FFA also accumulate in experimental steatohepatitis, further supporting a role for these nutrients in hepatic lipotoxicity (17).…”

mentioning

confidence: 99%

Mcl-1 Degradation during Hepatocyte Lipoapoptosis

Masuoka

Mott

Bronk

et al. 2009

Journal of Biological Chemistry

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Current evidence suggests that hepatic steatosis is present in up to 30% of the American population (1). A subset of these individuals develop severe hepatic lipotoxicity, a syndrome referred to as NASH 2 (2), which can progress to cirrhosis and its chronic sequela (3, 4). A major risk factor for hepatic lipotoxicity is insulin resistance (5-7), resulting in excessive lipolysis within peripheral adipose tissue with release of high levels of free fatty acids (FFA) to the circulation. Circulating FFA are taken up by the liver via fatty acid transporter 5 and CD36 (8 -10), and the bulk of hepatic neutral fat is derived from reesterification of circulating FFA (8). Current concepts indicate that FFA, and not their esterified product (triglyceride), mediate hepatic lipotoxicity (11,12). Elevated serum FFA correlate with liver disease severity (13-15), and therapies that enhance insulin sensitivity ameliorate hepatic lipotoxicity, in part, by decreasing plasma FFA (16). Hepatic FFA also accumulate in experimental steatohepatitis, further supporting a role for these nutrients in hepatic lipotoxicity (17). Saturated FFA are more strongly implicated in hepatic lipotoxicity than unsaturated FFA (18,19). Saturated FFA induce hepatocyte apoptosis (20, 21), a cardinal feature of nonalcoholic fatty liver disease (22), and serum biomarkers of apoptosis are useful for identifying hepatic lipotoxicity (23). Thus, FFA-mediated lipotoxicity occurs, in part, by apoptosis.Apoptosis is regulated by members of the Bcl-2 protein family (24). These proteins can be categorized into three subsets as follows: the guardians or anti-apoptotic members of this family, which include Bcl-2, A1, Mcl-1, Bcl-x L , and Bcl-w; the multidomain executioners or proapoptotic members of this family, which include Bax and Bak; and the messengers or biosensors of cell death, which share only the third Bcl-2 homology domain and are referred to as BH3-only proteins. This last group of proteins includes Bid, Bim, Bmf, Puma, Noxa, Hrk, Bad, and Bik. We have previously reported that cytotoxic FFA induce Bim expression by a FoxO3a-dependent mechanism that contributes, in part, to lipoapoptosis by activating Bax (20,21). However, Bax activation can be held in check by anti-apoptotic members of the Bcl-2 family suggesting their function may also be dysregulated during FFA-mediated cytotoxicity.Bcl-2 is not expressed in hepatocytes at the protein level (25), whereas Bcl-w and Bfl-1/A1 knock-out mice have no liver phenotype (26 -28). However, both potent anti-apoptotic proteins Bcl-x L and Mcl-1 are expressed by hepatocytes and exhibit a liver phenotype in knock-out mice (29, 30), whereas up-regulation of Mcl-1 renders hepatocytes resistant to apoptosis (31-33). It has also been posited that cellular elimination of Mcl-1 is a critical step in certain proapoptotic cascades (34,35). Mcl-1 is unique among Bcl-2 proteins in that it has a short half-life, 30 -120 min in most cell types, due to the presence of two sequences rich in proline, glutamic acid, serine, and threo...

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