Breast-feeding is associated with a lower risk of developing obesity during childhood and adulthood compared with feeding infant milk formula (IMF). Previous studies have shown that an experimental IMF (eIMF; comprising Nuturis®) programmed mouse pups for a lower body weight and fat mass gain in adulthood when challenged with a high-fat diet (HFD) compared with a control IMF (cIMF). Nuturis has a lipid composition and structure more similar to breast milk. Here, the long-term effects were tested of a similar eIMF, but with an adapted lipid composition and a cIMF, on body weight, glucose homoeostasis, liver and adipose tissue. Nutrient composition was similar for the eIMF and cIMF; the lipid fractions comprised approximately 50 % milk fat. C57BL/6JOlaHsd mice were fed cIMF or eIMF from postnatal day (PN) 16–42 followed by an HFD until PN168. Feeding eIMF v. cIMF in early life resulted in a lower body weight (–9 %) and body fat deposition (–14 %) in adulthood (PN105). The effect appeared transient, as from PN126 onwards, after 12 weeks’ HFD, eIMF-fed mice caught up on controls and body and fat weights became comparable between groups. Glucose and energy metabolism were similar between groups. At dissection (PN168), eIMF-fed mice showed larger (+27 %) epididymal fat depots and a lower (–26 %) liver weight without clear morphological aberrations. Our data suggest the size and coating but not the lipid composition of IMF fat globules underlie the programming effect observed. Prolonged exposure to an HFD challenge partly overrules the programming effect of early diet.
BaCKgRoUND aND aIMS:Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. appRoaCH aND ReSUltS: To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL −/− ) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2 −/− ) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/ transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL −/− mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and β-oxidation. Notably, pharmacological ( JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2 −/− mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E 2 accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation.CoNClUSIoNS: Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis.
Background and Aims Increased fatty acid (FA) flux from adipose tissue to the liver contributes to the development of NAFLD. Because free FAs are key lipotoxic triggers accelerating disease progression, inhibiting adipose triglyceride lipase (ATGL)/patatin‐like phospholipase domain containing 2 (PNPLA2), the main enzyme driving lipolysis, may attenuate steatohepatitis. Approach and Results Hepatocyte‐specific ATGL knockout (ATGL LKO) mice were challenged with methionine‐choline–deficient (MCD) or high‐fat high‐carbohydrate (HFHC) diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis, and endoplasmic reticulum (ER) stress markers were investigated. DNA binding activity for peroxisome proliferator‐activated receptor (PPAR) α and PPARδ was measured. After short hairpin RNA–mediated ATGL knockdown, HepG2 cells were treated with lipopolysaccharide (LPS) or oleic acid:palmitic acid 2:1 (OP21) to explore the direct role of ATGL in inflammation in vitro. On MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared with challenged wild‐type (WT) mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary‐challenged ATGL LKO mice showed lower hepatic inflammation, reflected by the reduced number of Galectin3/MAC‐2 and myeloperoxidase‐positive cells and low mRNA expression levels of inflammatory markers (such as IL‐1β and F4/80) when compared with WT mice. In line with this, protein levels of the ER stress markers protein kinase R–like endoplasmic reticulum kinase and inositol‐requiring enzyme 1α were reduced in ATGL LKO mice fed with MCD diet. Accordingly, pretreatment of LPS‐treated HepG2 cells with the PPARδ agonist GW0742 suppressed mRNA expression of inflammatory markers. Additionally, ATGL knockdown in HepG2 cells attenuated LPS/OP21‐induced expression of proinflammatory cytokines and chemokines such as chemokine (C‐X‐C motif) ligand 5, chemokine (C‐C motif) ligand (Ccl) 2, and Ccl5. Conclusions Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis.
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