title: Proteome Dynamics Reveals Pro-Inflammatory Remodeling of Plasma Proteome in a Mouse Model of NAFLD.
abstract: Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. Because the liver is the major source of circulatory proteins, it is not surprising that hepatic disease could lead to alterations in the plasma proteome, which are therein implicated in atherosclerosis. The current study used low-density lipoprotein receptor-deficient (LDLR(-/-)) mice to examine the impact of Western diet (WD)-induced NAFLD on plasma proteome homeostasis. Using a (2)H2O-metabolic labeling method, we found that a WD led to a proinflammatory distribution of circulatory proteins analyzed in apoB-depleted plasma, which was attributed to an increased production. The fractional turnover rates of short-lived proteins that are implicated in stress-response, lipid metabolism, and transport functions were significantly increased with WD (P < 0.05). Pathway analyses revealed that alterations in plasma proteome dynamics were related to the suppression of hepatic PPARα, which was confirmed based on reduced gene and protein expression of PPARα in mice fed a WD. These changes were associated with ∼4-fold increase (P < 0.0001) in the proinflammatory property of apoB-depleted plasma. In conclusion, the proteome dynamics method reveals proinflammatory remodeling of the plasma proteome relevant to liver disease. The approach used herein may provide a useful metric of in vivo liver function and better enable studies of novel therapies surrounding NAFLD and other diseases.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Nutrition, Center for Proteomics and Bioinformatics, Electrical Engineering and Computer Science Department, Case Western Reserve University , Cleveland, Ohio 44195, United States.
authors.forename: Gurkan
authors.initials: G
authors.lastname: Bebek
authors.affiliation: School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Previs
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.affiliation: The University of Texas Medical Branch , Galveston, Texas 77555, United States.
authors.forename: Rovshan G
authors.initials: RG
authors.lastname: Sadygov
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: McCullough
authors.forename: Belinda
authors.initials: B
authors.lastname: Willard
authors.forename: Takhar
authors.initials: T
authors.lastname: Kasumov
mesh_terms: D000818:Animals; D066273:Diet, Western; D004195:Disease Models, Animal; D018836:Inflammation Mediators; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood*; D047493:PPAR alpha / Q000378:metabolism; D010949:Plasma / Q000737:chemistry / Q000378:metabolism; D020543:Proteome / Q000032:analysis / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: D018836:Inflammation Mediators; D047493:PPAR alpha; D020543:Proteome; D011973:Receptors, LDL
keywords: HDL; NAFLD; atherosclerosis; heavy water; proteome dynamics