(Pro)Renin Receptor Antagonism Attenuates High-Fat-Diet–Induced Hepatic Steatosis
article
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic steatosis and fibrosis. C57Bl/6J mice were fed a high-fat diet (HFD) or normal-fat diet (NFD) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either the peptide PRR antagonist, PRO20, or scrambled peptide for 4 or 6 weeks. Mice fed a 6-week HFD exhibited increased liver lipid accumulation and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or blood glucose. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase, an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPAR[gamma] and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the involvement of the PRR in liver triglyceride synthesis and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis in NAFLD. (C) 2023 by the authors.
Topics
(Pro)renin receptorglycerol-3-phosphate acyltransferase 3NAFLDperoxisome proliferator activated receptor γacetyl coenzyme A carboxylaseadenosine triphosphate citrate synthasealanine aminotransferaseangiotensin II antagonistaspartate aminotransferasebeta actinbinding proteincarbohydrate response element binding proteinfatty acid synthaseglycerol 3 phosphate acyltransferaseglycerol 3 phosphate acyltransferase 3isofluraneliver X receptor alphalosartanperoxisome proliferator activated receptor alphaperoxisome proliferator activated receptor deltaperoxisome proliferator activated receptor gammaprorenin receptorsterol regulatory element binding protein 1csterol regulatory element binding protein 2triacylglycerolunclassified drugcholinemethionineN-formyl-13-dihydrocarminomycinprorenin receptortriacylglycerolanimal experimentanimal modelanimal tissuecontrolled studydrug antagonismenzyme activityfasting blood glucose levelfatty liverglucose blood levelglucose metabolismglucose tolerance testlipid dietlipid metabolismlipid storageliver fibrosisliver injuryliver tissuemalemethionine/choline deficient dietmicroscopymicrovesicular steatosismousenonalcoholic fatty livernonhumanphenotypereverse transcription polymerase chain reactionRNA extractionRNA isolationspectrophotometryWestern blottingadverse eventanimalC57BL mousefibrosislipid dietmetabolismnonalcoholic fatty liverAnimalsCholineDiet, High-FatFibrosisLipidsLiverMethionineMiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseProrenin ReceptorTriglycerides
TNO Identifier
982256
ISSN
2218273X
Source
Biomolecules, 13(1)
Article nr.
142