Non-alcoholic fatty liver disease (NAFLD), the most common of liver pathologies, is one of the most profound health disparities. The molecular pathway(s) associated with the pathogenesis of NAFLD and its subsequentprogressiontononalcoholicsteatohepatitis(NASH)remainselusive.Wehavepreviouslyshownthat Carcinoembryonicantigen-relatedcelladhesionmolecule1(CEACAM1)playsacriticalroleininsulinclearance in the liver and links hyperinsulinemia to NAFLD/NASH. Preliminary data identify that Cell death-Inducing DFF45-likeEffector(Cidec;?alsotermedFsp27),alipiddropletassociatedproteinthatregulateslipolysisinthe adiposetissue,regulateslivermetabolicfunctionandfibrosisviahepaticCEACAM1.Mostinterestingly,wefound that FSP27?/? mice exhibited lower hepatic CEACAM1 levels on regular and HF diets, and subsequently, impairedinsulinclearanceandhyperinsulinemiathatcouldinturn,mediatehepaticinsulinresistance.Inaddition to hyperinsulinemia-driven hepatic steatosis, Fsp27?/? mice also exhibited elevated plasma Endothelin 1 and spontaneoushepaticbridging-fibrosis,comparabletothephenotypeofCeacam1knockoutmice.Tostudythe gain-of-functionwehavedevelopedaninnovativeadipose-specifictransgenicmousemodelexpressinghuman- FSP27. Our preliminary data show that this mouse model exhibits normal insulin and glucose tolerance in response to HF intake in parallel to a remarkable ~5-fold induction of hepatic CEACAM1 protein levels. Since lipolysis-derivedfattyacidsfromwhiteadiposetissue(WAT)reduceshepaticCEACAM1expressionandforced liver-specificoverexpressionofCEACAM1oritsadenoviral-mediateddeliveryprotectsagainstHFdiet-induced insulinresistanceandsteatohepatitis,andfibrosisinWATandliver,wehypothesizethatreductionofFSP27in adipocytes causes FFA release and redistribution to the liver to reduce hepatic CEACAM1 levels and subsequently,causehepatocyteinjuryandhepaticfibrosis.Wepostulatetheunderlyingmechanismstoinvolve activation of epidermal growth factor receptor by fatty acids and Endothelin 1, the expression of which is upregulated by the MEK/ERK-PPARg? pathway.
Aim 1 will investigate whether CEACAM1 in hepatocytes regulates hepatic fibrosis in mice with adipocyte-specific deletion of Fsp27 (paracrine regulation).
Aim 2 will examinethecell-autonomousfibrogeniceffectofFSP27deletioninhepaticstellatecells.Thisapproachiswell- thoughtandwell-designedwherenovelmousemodels(bothknockoutandtransgenic)willbeusedtostudythecross- talk between adipose tissue and liver which plays a critical role in the development of hepatic fibrosis via altering FSP27.AstrengthofthisproposalisaninterdisciplinarycollaborationbetweenDrs.S.Najjar(fattyliverdisease andlipidmetabolism)andV.Puri(adiposebiologyandlipidmetabolism).Asisclearfromthestrongpreliminarydata, these scientists have productively collaborated on a proposal that will delineate the novel pathways in the pathogenesisofNAFLD/NASHthatmightleadtonoveltreatmentsagainstthisremarkablehealthproblem.

Public Health Relevance

Nonalcoholic fatty liver disease (NAFLD) is the fastest growing cause of liver dysfunction with more than 80 million Americans (30-40%) being affected, and nearly 10 million being diagnosed with Non-alcoholic steatohepatitis (NASH). Its progressive form [nonalcoholic steatohepatitis (NASH)] is associated with hepatic fibrosis that can develop into cirrhosis. The proposed studies will identify genes associated with a cross-talk between adipose tissue and liver that plays a critical role in the pathogenesis and pathophysiology of NAFLD/NASH. The ultimate goal of these studies is to identify novel pathway(s) in the pathogenesis of fibrosis to develop appropriate therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK124126-01A1
Application #
9998569
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2020-04-01
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Ohio University Athens
Department
Other Basic Sciences
Type
Schools of Osteopathic Medicine
DUNS #
041077983
City
Athens
State
OH
Country
United States
Zip Code
45701