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

Role of oleic acid in the gut-liver axis: From diet to the regulation of its synthesis via Stearoyl-CoA desaturase 1 (SCD1)

The consumption of an olive oil rich diet has been associated with the diminished incidence of cardiovascular disease and cancer. Several studies have attributed these beneficial effects to oleic acid (C18 n-9), the predominant fatty acid principal component of olive oil. Oleic acid is not an essential fatty acid since it can be endogenously synthesized in humans. Stearoyl-CoA desaturase 1 (SCD1) is the enzyme responsible for oleic acid production and, more generally, for the synthesis of monounsaturated fatty acids (MUFA). The saturated to monounsaturated fatty acid ratio affects the regulation of cell growth and differentiation, and alteration in this ratio has been implicated in a variety of diseases, such as liver dysfunction and intestinal inflammation. In this review, we discuss our current understanding of the impact of gene-nutrient interactions in liver and gut diseases, by taking advantage of the role of SCD1 and its product oleic acid in the modulation of different hepatic and intestinal metabolic pathways

Phase I clinical trial to evaluate TOTUM-63, a botanical complex for managing prediabetes

International audienceThe IDF estimates that the number of individuals with diabetes will rise by almost 55% to 640 million by 2040. According to the ADA, 86 million Americans aged 20 years and over are prediabetic. We have developed an innovative botanical complex (BC) that aims to reverse prediabetes and to prevent each dysfunction and/or its consequences independently. The ability of the BC to control fasting glycemia, HbA1c, insulin sensitivity, serum and hepatic triglycerides, and weight gain through a specific effect on fat mass has been demonstrated in different animal models (db/db, C57BL/6 high fat diet, C57BL/6NR and Syrian hamster normal diet). Following these results, a first Phase I open trial was initiated on slightly overweight male volunteers (NCT02790489). The study included an initial period of supplementation with 2.5g/ day of the BC for 4 weeks (V1; V2:V1+4weeks) followed by an intermediary analysis and a wash-out period of 2 weeks, then 4 weeks of supplementation with 5.0g/day (V3, V2+2weeks; V4:V3+4weeks). Different safety parameters, in particular hepatic, urinary, renal and hemodynamic, were assessed at all visits. Glycemia and insulinemia were also monitored from catheter samples after taking a standardized breakfast (Breakfast Tolerance Test: BTT) at V3 and V4. Fourteen volunteers completed the trial; 1 volunteer left the study after V2 due to a persistent health problem identified on inclusion that was independent of the BC. The results do not show any clinically significant increase in the various safety parameters, objectifying the very good tolerance of the BC for the two doses tested. In addition, BC did not induce an increase in insulin secretion during the BTT. Conversely, we observed a decrease in the insulinemia AUC (V4:3286±624 versus V3:5445±1240mUI.min/L,-40%, p=0.02), and a downward trend for the glycemia AUC (V4:118±28 versus V3:168±28mmol.min/L,-30%, p=0.08). The candidate BC is currently undergoing a Phase 2a trial on 80 prediabetic subjects with abdominal obesity (NCT02868177)

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