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The peroxisome proliferator-activated receptor ␣ (PPAR ␣ ) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPAR ␣ is activated as a component of the cellular lipid homeostatic response, the expression of PPAR ␣ target genes was characterized in response to a perturbation in cellular lipid oxidative flux caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition of fatty acid oxidative flux caused a feedback induction of PPAR ␣ target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPAR ␣ (PPAR ␣Ϫ / Ϫ ), inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of male, but only 25% of female PPAR ␣Ϫ / Ϫ mice. The metabolic phenotype of male PPAR ␣Ϫ / Ϫ mice was rescued by a 2-wk pretreatment with ␤ -estradiol. These results demonstrate a pivotal role for PPAR ␣ in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism. ( J.

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S6 kinase (S6K) deletion in metazoans causes small cell size, insulin hypersensitivity, and metabolic adaptations; however, the underlying molecular mechanisms are unclear. Here we show that S6K-deficient skeletal muscle cells have increased AMP and inorganic phosphate levels relative to ATP and phosphocreatine, causing AMP-activated protein kinase (AMPK) upregulation. Energy stress and muscle cell atrophy are specifically triggered by the S6K1 deletion, independent of S6K2 activity. Two known AMPK-dependent functions, mitochondrial biogenesis and fatty acid beta-oxidation, are upregulated in S6K-deficient muscle cells, leading to a sharp depletion of lipid content, while glycogen stores are spared. Strikingly, AMPK inhibition in S6K-deficient cells restores cell growth and sensitivity to nutrient signals. These data indicate that S6K1 controls the energy state of the cell and the AMPK-dependent metabolic program, providing a mechanism for cell mass accumulation under high-calorie diet.

This study suggests a rationale for a possible correction of moderate RC disorders due to mutations in nuclear genes, using existing drugs, and brings new insights into the role of PPAR in the regulation of the mitochondrial RC in human cells.

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Background Comprehensive transcriptomic analyses have shown that colorectal cancer (CRC) is heterogeneous and have led to the definition of molecular subtypes among which the stem-cell, mesenchymal-like group is associated with poor prognosis. The molecular pathways orchestrating the emergence of this subtype are incompletely understood. In line with the contribution of the cellular prion protein PrP C to stemness, we hypothesize that deregulation of this protein could lead to a stem-cell, mesenchymal-like phenotype in CRC. Methods We assessed the distribution of the PrP C -encoding PRNP mRNA in two large CRC cohorts according to molecular classification and its association with patient survival. We developed cell-based assays to explore the impact of gain and loss of PrP C function on markers of the mesenchymal subtype and to delineate the signalling pathways recruited by PrP C . We measured soluble PrP C in the plasmas of 325 patients with metastatic CRC and probed associations with disease outcome. Findings We found that PRNP gene expression is enriched in tumours of the mesenchymal subtype and is associated with poor survival. Our in vitro analyses revealed that PrP C controls the expression of genes that specify the mesenchymal subtype through the recruitment of the Hippo pathway effectors YAP and TAZ and the TGFß pathway. We showed that plasma levels of PrP C are elevated in metastatic CRC and are associated with poor disease control. Interpretation Our findings define PrP C as a candidate driver of the poor-prognosis mesenchymal subtype of CRC. They suggest that PrP C may serve as a potential biomarker for patient stratification in CRC. Funding Grant support was provided by the following: (grant number 2016-1-EMERG-36-UP 5-1), (grant number PJA 20171206220), (grant number 415) as well as .