HDL Flux is Higher in Patients with Nonalcoholic Fatty Liver Disease
haevy water; HDL; NAFLD; NASH; proteomics
October 2019 Update
Altered lipid metabolism and inflammation are involved in the pathogenesis of both non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD). Even though high-density lipoprotein (HDL), a CVD protective marker, is decreased, whether HDL metabolism and function are perturbed in NAFLD are currently unknown. We examined the effect of NAFLD and disease severity on HDL metabolism and function in patients with biopsy-proven simple steatosis (SS), nonalcoholic steatohepatitis (NASH), and healthy controls. HDL turnover and HDL proteins dynamics in SS (n=7), NASH patients (n=8), and healthy controls (n=9) were studied in vivo. HDL maturation and remodeling, anti-oxidant, cholesterol efflux properties, and activities of lecithin cholesterol ester acyl transferase (LCAT) and cholesterol ester transfer protein (CETP) were quantified using in vitro assays. All NAFLD patients had increased turnover of both HDL cholesterol (HDLc, 0.16±0.09 vs. 0.34±0.18 day-1, P<0.05) and ApoAI (0.26±0.04 vs. 0.34±0.06 day-1, P<0.005) compared to healthy controls. The fractional catabolic rates (FCR) of other HDL proteins, including ApoAII (and ApoAIV were higher (P<0.05) in NAFLD patients who also had higher CETP activity, ApoAI/HDLc ratio (P<0.05). NAFLD-induced alterations were associated with lower antioxidant (114.2±46.6 vs 220.5±48.2 nml/ml●min) but higher total efflux properties of HDL (23.4±1.3 vs. 25.5±2.3 %) (both P<0.05) which was more pronounced in individuals with NASH. However, no differences were observed in either HDL turnover, antioxidant and cholesterol efflux functions of HDL or HDL proteins' turnover between SS and NASH subjects. Thus, HDL metabolism and function are altered in NAFLD without any significant differences between SS and NASH.
McCullough Arthur; Previs Stephen F; Dasarathy Jaividhya; Lee Kwangwon; Osme Abdullah; Kim Chunki; Ilchenko Serguei; Lorkowski Shuhui W; Smith Jonathan D; Dasarathy Srinivasan; Kasumov Takhar
American Journal of Physiology. Endocrinology and Metabolism
2019
2019-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpendo.00193.2019" target="_blank" rel="noreferrer noopener">10.1152/ajpendo.00193.2019</a>
Proteome Dynamics Reveals Pro-inflammatory Remodeling Of Plasma Proteome In A Mouse Model Of Nafld
antiinflammatory properties; Atherosclerosis; Biochemistry & Molecular Biology; fatty liver-disease; gene-expression; HDL; heavy water; high-density-lipoprotein; mass-spectrometry; NAFLD; oxidized phospholipids; ppar-alpha; proteome dynamics; proteomics; rapid method; shotgun; statistical-model
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 (H2O)-H-2-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 PPAR alpha, which was confirmed based on reduced gene and protein expression of PPAR alpha in mice fed a WD. These changes were associated with similar to 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.
Li L; Bebek G; Previs S F; Smith J D; Sadygov R G; McCullough A J; Willard B; Kasumov T
Journal of Proteome Research
2016
2016-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1021/acs.jproteome.6b00601" target="_blank" rel="noreferrer noopener">10.1021/acs.jproteome.6b00601</a>