Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD.

OBJECTIVE: Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor expressed in tissues with high oxidative activity that plays a central role in metabolism. In this work, we investigated the effect of hepatocyte PPARα on non-alcoholic fatty liver disease (NAFLD). DESIGN: We constructed a novel hepatocyte-specific PPARα knockout (Pparα(hep-/-)) mouse model. Using this novel model, we performed transcriptomic analysis following fenofibrate treatment. Next, we investigated which physiological challenges impact on PPARα. Moreover, we measured the contribution of hepatocytic PPARα activity to whole-body metabolism and fibroblast growth factor 21 production during fasting. Finally, we determined the influence of hepatocyte-specific PPARα deficiency in different models of steatosis and during ageing. RESULTS: Hepatocyte PPARα deletion impaired fatty acid catabolism, resulting in hepatic lipid accumulation during fasting and in two preclinical models of steatosis. Fasting mice showed acute PPARα-dependent hepatocyte activity during early night, with correspondingly increased circulating free fatty acids, which could be further stimulated by adipocyte lipolysis. Fasting led to mild hypoglycaemia and hypothermia in Pparα(hep-/-) mice when compared with Pparα(-/-) mice implying a role of PPARα activity in non-hepatic tissues. In agreement with this observation, Pparα(-/-) mice became overweight during ageing while Pparα(hep-/-) remained lean. However, like Pparα(-/-) mice, Pparα(hep-/-) fed a standard diet developed hepatic steatosis in ageing. CONCLUSIONS: Altogether, these findings underscore the potential of hepatocyte PPARα as a drug target for NAFLD

Does chronic treatment with paracetamol have nutritional consequence in elderly subjects?

International audienc

Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia

International audienc

Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling.

Olive oil consumption is beneficial for health as it is associated with a decreased prevalence of cancer and cardiovascular diseases. Oleic acid is, by far, the most abundant component of olive oil. Since it can be made through de novo synthesis in animals, it is not an essential fatty acid. While it has become clear that dietary oleic acid regulates many biological processes, the signaling pathway involved in these regulations remains poorly defined. In this work we tested the impact of an oleic acid-rich diet on hepatic gene expression. We were particularly interested in addressing the contribution of Liver X Receptors (LXR) in the control of genes involved in hepatic lipogenesis, an essential process in whole body energy homeostasis. We used wild-type mice and transgenic mice deficient for both α and β Liver X Receptor isoforms (LXR-/-) fed a control or an oleate enriched diet. We observed that hepatic-lipid accumulation was enhanced as well as the expression of lipogenic genes in the liver of wild-type mice fed the oleate enriched diet. In contrast, none of these changes occurred in the liver of LXR-/- mice. Strikingly, oleate-rich diet reduced cholesterolemia in wild-type mice and induced signs of liver inflammation and damage in LXR-/- mice but not in wild-type mice. This work suggests that dietary oleic acid reduces cholesterolemia while promoting LXR-dependent hepatic lipogenesis without detrimental effects to the liver

Deletion of Stearoyl-CoA Desaturase-1 From the Intestinal Epithelium Promotes Inflammation and Tumorigenesis, Reversed by Dietary Oleate

Background & Aims: The enzyme stearoyl-coenzyme A desaturase 1 (SCD or SCD1) produces monounsaturated fatty acids by introducing double bonds into saturated bonds between carbons 9 and 10, with oleic acid as the main product. SCD1 is present in the intestinal epithelium, and fatty acids regulate cell proliferation, so we investigated the effects of SCD1-induced production of oleic acid in enterocytes in mice. Methods: We generated mice with disruption of Scd1 selectively in the intestinal epithelium (iScd1–/– mice) on a C57BL/6 background; iScd1+/+ mice were used as controls. We also generated iScd1–/–ApcMin/+ mice and studied cancer susceptibility. Mice were fed a chow, oleic acid–deficient, or oleic acid–rich diet. Intestinal tissues were collected and analyzed by histology, reverse transcription quantitative polymerase chain reaction, immunohistochemistry, and mass spectrometry, and tumors were quantified and measured. Results: Compared with control mice, the ileal mucosa of iScd1–/– mice had a lower proportion of palmitoleic (C16:1 n-7) and oleic acids (C18:1 n-9), with accumulation of stearic acid (C18:0); this resulted a reduction of the Δ9 desaturation ratio between monounsaturated (C16:1 n-7 and C18:1 n-9) and saturated (C16:0 and C18:0) fatty acids. Ileal tissues from iScd1–/– mice had increased expression of markers of inflammation activation and crypt proliferative genes compared with control mice. The iScd1–/– ApcMin/+ mice developed more and larger tumors than iScd1+/+ApcMin/+ mice. iScd1–/–ApcMin/+ mice fed the oleic acid-rich diet had reduced intestinal inflammation and significantly lower tumor burden compared with mice fed a chow diet. Conclusions: In studies of mice, we found intestinal SCD1 to be required for synthesis of oleate in the enterocytes and maintenance of fatty acid homeostasis. Dietary supplementation with oleic acid reduces intestinal inflammation and tumor development in mice

LXR protects from hepatic damage induced by an oleic-rich diet.

<p>(A) <i>Tnf</i>α, <i>Ccl2</i>, <i>F4/80</i>, <i>Cd68</i> and <i>Il1β</i> mRNA quantification assayed by qPCR. (B) Plasma activity of ALT and AST. (C) Plasma cholesterol and lathosterol levels analyzed by gas chromatography. Data are the mean±SEM of values measured in LXR+/+ and LXR-/- mice fed the REF or the OLIV diet. ^a Significant genotype effect. ^b Significant difference versus REF diet (n = 6 mice per group).</p

High oleic acid diet modulates hepatic gene expression.

<p>Hepatic gene expression of 142 genes related to lipid metabolism, nuclear receptor signaling and inflammation were quantified by qPCR from liver of LXR+/+ and LXR-/- mice fed the REF or the OLIV diet. Data are presented as a heatmap associated with a hierarchical classification.</p

Effects of an oleic acid-rich diet on hepatic fatty acid profile in LXR+/+ and LXR-/- mice.

<p>Effects of an oleic acid-rich diet on hepatic fatty acid profile in LXR+/+ and LXR-/- mice.</p

LXR mediate the induction of lipogenesis induced by an oleic acid-rich diet.

<p>(A) Hepatic <i>Acly</i>, <i>Acaca</i>, <i>Acacb</i>, <i>Fasn</i>, <i>Elovl6</i>, <i>Scd1</i> mRNA levels quantified by qPCR. (B) Cytoplasmic protein expression levels of P-ACLY, ACLY, ACC, ELOVL6, SCD1, FASN AND β-ACTIN assayed by Western Blotting. (C) <i>Fads1</i>, <i>Fads2</i>, <i>Elovl5</i>, <i>Gpat</i>, <i>Pnpla3</i> and <i>Lpk</i> mRNA quantification assayed by qPCR. (D) <i>Srebp-1c</i> and <i>Chrebp</i> mRNA quantification assayed by qPCR. (E) Cytoplasmic and nuclear expression levels of LXR, SREBP-1c and ChREBP assayed by Western Blotting. Data are the mean±SEM of values measured in LXR+/+ and LXR-/- mice fed REF or OLIV diet. ^a Significant genotype effect. ^b Significant difference versus REF diet (n = 6 mice per group).</p