Proteome Dynamics Reveals Pro-Inflammatory Remodeling of Plasma Proteome in a Mouse Model of NAFLD

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 2H2O-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.