Linking fat metabolism to hepatic fibrosis

将脂肪代谢与肝纤维化联系起来

• 批准号: 10601006
• 负责人: Sonia M. Najjar
• 金额: $ 51.57万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10601006
• 关键词: Adipocytes; Adipose tissue; Affect; Agonist; Alcoholic Fatty Liver; American; Animal Model; Apoptosis; Benign; Biology; Cell Death Induction; Cells; Central obesity; Characteristics; Chickens; Chronic; Cirrhosis; Clinical Research; Collaborations; Data; Development; Diagnosis; Diet; Disease; Endothelin-1; Epidermal Growth Factor Receptor; Exhibits; Fatty Acids; Fatty Liver; Fibrosis; Functional disorder; Genes; Glycerol; Goals; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; High Fat Diet; Histologic; Human; Hyperinsulinism; Hypertriglyceridemia; Impairment; Inflammatory; Insulin; Insulin Resistance; Intake; Knock-out; Knockout Mice; Link; Lipase; Lipids; Lipolysis; Liver; Liver Dysfunction; Liver Fibrosis; Liver diseases; MEKs; Mediating; Metabolic; Modality; Molecular; Mus; Mutant Strains Mice; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Pioglitazone; Plasma; Play; Process; Productivity; Proteins; Regulation; Repression; Risk Factors; Role; Scientist; Signal Transduction; Steatohepatitis; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; United States; Water; Weight Gain; adenoviral mediated; carcinoembryonic antigen-related cell adhesion molecules; design; drug development; experimental study; fatty liver disease; gain of function; glucose tolerance; health disparity; hepatocyte injury; innovation; insulin receptor tyrosine kinase; insulin sensitivity; insulin tolerance; interdisciplinary collaboration; knock-down; lipid biosynthesis; lipid metabolism; liver inflammation; metabolic phenotype; mouse model; mutant; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; null mutation; overexpression; paracrine; receptor; reconstitution; response; stellate cell; therapeutic target; uptake

Project Summary    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  subsequent progression to nonalcoholic steatohepatitis (NASH) remains elusive. We have previously shown that  Carcinoembryonic antigen-­related cell adhesion molecule 1 (CEACAM1) plays a critical role in insulin clearance  in  the  liver  and  links  hyperinsulinemia  to  NAFLD/NASH.    Preliminary  data  identify  that  Cell  death-­Inducing  DFF45-­like Effector (Cidec;; also termed Fsp27), a lipid droplet associated protein that regulates lipolysis in the  adipose tissue, regulates liver metabolic function and fibrosis via hepatic CEACAM1. Most interestingly, we found  that  FSP27–/–  mice  exhibited  lower  hepatic  CEACAM1  levels  on  regular  and  HF  diets,  and  subsequently,  impaired insulin clearance and hyperinsulinemia that could in turn, mediate hepatic insulin resistance. In addition  to  hyperinsulinemia-­driven  hepatic  steatosis,  Fsp27–/–  mice  also  exhibited  elevated  plasma  Endothelin  1  and  spontaneous hepatic bridging-­fibrosis, comparable to the phenotype of Ceacam1 knockout mice. To study the  gain-­of-­function we have developed an innovative adipose-­specific transgenic mouse model expressing human-­ 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-­derived fatty acids from white adipose tissue (WAT) reduces hepatic CEACAM1 expression and forced  liver-­specific overexpression of CEACAM1 or its adenoviral-­mediated delivery protects against HF diet-­induced  insulin resistance and steatohepatitis, and fibrosis in WAT and liver, we hypothesize that reduction of FSP27 in  adipocytes  causes  FFA  release  and  redistribution  to  the  liver  to  reduce  hepatic  CEACAM1  levels  and  subsequently, cause hepatocyte injury and hepatic fibrosis. We postulate the underlying mechanisms to involve  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  examine the cell-­autonomous fibrogenic effect of FSP27 deletion in hepatic stellate cells.  This approach is well-­ thought and well-­designed where novel mouse models (both knockout and transgenic) will be used to study the cross-­ talk  between  adipose  tissue  and  liver  which  plays  a  critical  role  in  the  development  of  hepatic  fibrosis  via  altering  FSP27. A strength of this proposal is an interdisciplinary collaboration between Drs. S. Najjar (fatty liver disease  and lipid metabolism) and V. Puri (adipose biology and lipid metabolism). As is clear from the strong preliminary data,  these  scientists  have  productively  collaborated  on  a  proposal  that  will  delineate  the  novel  pathways  in  the  pathogenesis of NAFLD/NASH that might lead to novel treatments against this remarkable health problem.

项目总结