6533b856fe1ef96bd12b1d4c
RESEARCH PRODUCT
Niemann-Pick type C2 protein supplementation in experimental non-alcoholic fatty liver disease
Claus Uhrenholt ChristensenDetlef SchuppanDetlef SchuppanHenning GrønbækSara HeebøllKaren Louise ThomsenEmilie GlavindYong Ook KimChristian W. HeegaardStephen Hamilton-dutoitsubject
0301 basic medicinePhysiologyGene Expressionlcsh:MedicinePathology and Laboratory MedicineBiochemistrychemistry.chemical_compound0302 clinical medicineNon-alcoholic Fatty Liver DiseaseFibrosisImmune PhysiologyMedicine and Health Scienceslcsh:ScienceImmune ResponseSterol Regulatory Element Binding ProteinsInnate Immune SystemMultidisciplinarybiologyLiver DiseasesReverse cholesterol transportFatty liverIntracellular Signaling Peptides and ProteinsLipidsCholesterolLiverCytokinesLiver FibrosisFemale030211 gastroenterology & hepatologylipids (amino acids peptides and proteins)Research Articlemedicine.medical_specialtyImmunologyBiological Transport ActiveGastroenterology and HepatologyCollagen Type I03 medical and health sciencesSigns and SymptomsDiagnostic MedicineInternal medicineGeneticsmedicineAnimalsRats WistarGlycoproteinsNutritionInflammationbusiness.industryCholesterollcsh:RBiology and Life Sciencesnutritional and metabolic diseasesMolecular Developmentmedicine.diseaseDietary FatsFibrosisRatsDietCollagen Type I alpha 1 ChainPPAR gammaFatty LiverDisease Models Animal030104 developmental biologyEndocrinologychemistryImmune SystemABCA1LDL receptorbiology.proteinlcsh:QSteatohepatitisCarrier ProteinsbusinessDevelopmental BiologyLipoproteindescription
BACKGROUND AND AIMS: Hepatic cholesterol deposition drives inflammation and fibrosis in non-alcoholic steatohepatitis (NASH). The Niemann-Pick type C2 (NPC2) protein plays an important role in regulating intracellular cholesterol trafficking and homeostasis. We hypothesized that intravenous NPC2 supplementation reduces cholesterol accumulation, hepatic inflammation and fibrogenesis in a nutritional NASH rat model.METHODS: Rats were fed a high-fat, high-cholesterol (HFHC) diet for four weeks resulting in moderately severe NASH. Animals were treated with intravenous NPC2 or placebo twice weekly for either the last two weeks or the entire four weeks. End-points were liver/body- and spleen/body weight ratios, histopathological NASH scores, fibrosis, serum liver enzymes, cholesterol, lipoproteins, cytokines, and quantitative polymerase chain reaction derived hepatic gene expression related to cholesterol metabolism, inflammation, and fibrosis.RESULTS: HFHC rats developed hepatomegaly, non-fibrotic NASH histopathology, elevated liver enzymes, serum cholesterol, and pro-inflammatory cytokines. Their sterol regulatory element binding factor 2 (SREBF2) and low-density lipoprotein receptor (LDL-R) mRNAs were down-regulated compared with rats on standard chow. NPC2 did not improve liver weight, histopathology, levels of serum liver enzymes or pro-inflammatory tumor necrosis factor-α (TNFα), Interleukin (IL)-6, or IL-1β in HFHC rats. Two weeks of NPC2 treatment lowered hepatic TNFα and COL1A1 mRNA expression. However, this effect was ultimately reversed following additional two weeks of treatment. Four weeks NPC2 treatment of rats raised ATP-binding cassette A1 (ABCA1) and low-density lipoprotein receptor (LDLR) mRNAs in the liver, concurrent with a strong tendency towards higher serum high-density lipoprotein (HDL). Furthermore, the peroxisome proliferator activated receptor-ɣ (PPARG) gene expression was reduced.CONCLUSIONS: NPC2 proved inefficient at modifying robust hepatic NASH end-points in a HFHC NASH model. Nonetheless, our data suggest that hepatic ABCA1 expression and reverse cholesterol transport were upregulated by NPC2 treatment, thus presenting putative therapeutic effects in diseases associated with deregulated lipid metabolism.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2017-12-20 |