Effect Of Neonatal Overfeeding On Lipid Metabolism And Its Programming Effect On NAFLD

Nonalcoholic fatty liver disease (NAFLD) is increasingly relevant public healthissues owing to their close association with the worldwide epidemics of obesity andmetabolic syndrome (MS). NAFLD ranges from asymptomatic steatosis tononalcoholic steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma,bringing a great harm for the long-time health in human. A large number studies haveconfirmed that the nutritional exposure in early life (infant and neonatal) not onlyrelates to children’s growth and development, but also impactes on adulthood health.Notably, early overnutrion is the risk factor for obesity and MS in adulthood. NAFLDis the hepatic manifestation of MS. Liver tissue developmental programming isconsidered to be the pathogenesis underlie this process, however, the exact molecularmechanism is unclear. Therefore, to explore the pathophysiological mechanisms ofearly nutritional programming, thereby reveal the prevention and treatment of adultdiseases during childhood, has become an urgent problem in health world.Growing evidences have suggested that lipid metabolism plays an important partin the regulation of hepatic lipid homeostasis. Hepatic lipid metabolism includes fattyacid uptake, synthesis, oxidation and export; involving in lipoprotein lipase (LPL),liver-type fatty acid-binding protein (L-FABP), acetyl-CoA carboxylase (ACC),carnitine palmitoyltransferase1(CPT1), microsomal triglyceride transfer protein(MTP) and so on. Hepatic steatosis develops when there is an imbalance in whichlipid availability (from fatty acid uptake or synthesis) exceed lipid disposal (via fattyacid oxidation or export).Previous studies had shown the critical windows of early nutrition programmingwere usually early fetal life, infancy or even adolescence. Liver is very sensitive to nutrients during the fetal period, and if damaged would increase the risk for majordiseases in adults. However, it is not sure whether early postnatal overfeeding alsoinfluences hepatic lipid metabolism and NAFLD. If so, what is the initiating time ofhepatic lipid metabolism developmental programming and the molecular mechanisms?Research on above problems will help us to understand the programming effect ofhepatic lipid metabolism and the window period of early nutrition programming, andthe relative molecular mechanisms. Thereby provide a new idea and practicalmolecular target on the prevention and treatment for nutrition programming.ObjectiveTo study the effects of neonatal overfeeding and postweaning high fat diet on theexpression of lipid metabolic associated enzymes and transcription factors in liverduring development, and its relationship between NAFLD in adult. Clarify theregulation mechanism and the window period of lipid metabolism in the earlynutrition programming.Methods1. Male Sprague-Dawley were redistributed to litter sizes of three (small litters, SL)or ten (normal litters, NL) on postnatal day3(P3). And then given either a control ora high fat (HF) diet from postnatal week3(W3) onward. Four groups were analyzed,namely NL, SL, NL-HF and SL-HF.2. Body weight, food intake, liver and fat pad (epididymal and retroperitonea) weight,glucose and lipid metabolism, liver triglyceride (TG) content and histologicalanalyses were recorded in W2, W3, W6, W10, W16, respectively.3. The mRNA expression of enzymes: ACC, LPL, L-FABP, CPT1, MTP andtranscription factors: sterol regulatory element-binding protein-1c (SREBP-1c) andperoxisome proliferator-activated receptor α (PPARα) in liver were determined byreal-time qPCR; the enzyme activity of ACC was determined by isotopic assay; theprotein expression of SREBP-1c and PPARα were determined by western-blot. Results1. As early as W3, SL rats began to elevated body weight, food intake and visceral fatpad (retroperitoneal and epididymal) compared with NL rats; and serum TG andcirculating levels of glucose were increased at W16. After wean, body weight, foodintake, fat pad and serum TG in SL-HF rats were persistent heavier than all othergroups, as well as impaired glucose tolerance. While NL-HF rats began to havegreater body weight, fat pad, serum TG and glucose tolerance at W10but were lessthan SL-HF rats during the experimental period. No matter exposed to NL or SLrearing, post-weaning HF diet increased the levels of serum TC and LDL, butdecreased HDL levels. Serum ALT and AST were remained unchanged in all groups.2. SL rats began to elevated HSI compared with NL rat sat W3, and hepatic TGcontent was increased at W16. SL-HF exposure resulted in the biggest increase inHSI and TG content from W6to W16, while NL-HF rats had greater HSI and TGcontent than NL rats at W16only. SL-HF offspring exhibited hepatic steatosis at W10.At W16, SL-HF livers were filled with large droplets and were accompanied withballooning and point necrosis in hepatocytes that had progressed from the10-weekpoint. While in NL-HF rats, small lipid droplets were observed at W16only.3. As early as W2, ACC mRNA expression in liver tissue was persistend higher in SLrats. From W10, hepatic ACC mRNA expression was further up-regulated in SL-HFrats; whereas NL-HF rats increased ACC expression at W10only. The ACC enzymeactivity paralled with mRNA expression. Hepatic LPL and L-FABP mRNAexpression were increased during lactation, but remain unchanged after weaning. Nomatter exposed to NL or SL rearing, HF diet reduced LPL, CPT1and MTP mRNAexpression at W16.4. Hepatic SREBP-1c mRNA expression increased in SL rats at W2. From W10,SREBP-1c mRNA expression was persistend higher in SL-HF rats. The mRNAexpression of PPARα was decreased in SL-HF at W10and W16only. The proteinexpression of SREBP-1c and PPARα paralled with mRNA expression. ConclusionPostnatal overfeeding promoted the early-onset and exaggeration of HF dietinduced NAFLD. Lactation is the critical window for the development programmingof fatty acid synthetase associated enzyme ACC. Postnatal overfeeding in ratsinduced continuously increase in ACC, a process might regulated by SREBP-1c.