Abstract
Hyperlipidemia is one of the major risk factors of atherosclerosis and other cardiovascular diseases. This study aimed to investigate the impact of leucine rich pentatricopeptide repeat containing protein (LRPPRC)-driven hepatic oxidative phoshorylation on blood lipid levels. The hepatic LRPPRC level was modulated by liver-specific transgenic or adeno-associated virus 8 carried shRNA targeting Lrpprc (aav-shLrpprc). Mice were fed with a high fat diet to induce obesity. Gene expression was analyzed by quantitative real-time PCR and / or western blot. The hepatic ATP level, hepatic and serum lipids contents, and mitochondria oxidative phosphorylation (OxPhos) complex activities were measured using specific assay kits. The uptake and oxidation of fatty acid by hepatocytes were assessed using 14C-palmitate. LRPPRC regulated the expression of genes encoded by mitochondrial genome but not those by nuclear genome involved in mitochondria biogenesis, OxPhos, and lipid metabolism. Increased OxPhos in liver mediated by LRPPRC resulted in the increase of hepatic ATP level. Lrpprc promoted palmitate uptake and oxidation by hypatocytes. The hepatic and serum triglyceride and total cholesterol levels were inversely associated with the hepatic LRPPRC level. These data demonstrated that LRPPRC-driven hepatic OxPhos could promote fatty acids uptake and oxidation by hepatocytes and reduce both hepatic and circulating triglyceride and cholesterol levels.
Highlights
Hyperlipidemia and hypertension are increasingly prevalent both in the United States (Go et al, 2014) and globally (Hanevold, 2013) in both adult and pediatric populations
As leucine rich pentatricopeptide repeat containing protein (LRPPRC) has been shown to regulate mitochondrial oxidative respiration, fatty acid oxidation, and hepatic lipid content (Liu et al, 2011; Mourier et al, 2014; Akie et al, 2015), this study aims to investigate whether changes in hepatic LRPPRC-driven mitochondrial oxidative phosphorylation (OxPhos) could impact hepatic and circulating lipid levels
Overexpression of LRPPRC in mouse liver significantly upregulated the transcript levels of genes encoded by mitochondrial genome (Figure 2A) but did not increase the mRNA levels of nuclear genes involved in either OxPhos (NDUFS1, SDHA, UQCRB, COX5A, and ATP5S) or mitochondrial biogenesis (PGC-1α, PGC-1β, ERRα, and Tfam) (Figure 2B)
Summary
Hyperlipidemia and hypertension are increasingly prevalent both in the United States (Go et al, 2014) and globally (Hanevold, 2013) in both adult and pediatric populations. Mitochondrial dysfunction increases predisposition to intracellular lipid accumulation (Morino et al, 2006; Schrauwen et al, 2010; Su et al, 2010) and non-alcoholic steatohepatitis (NASH) (Cortez-Pinto et al, 1999; Sanyal et al, 2001; Pérez-Carreras et al, 2003; Rector et al, 2010). Mitochondrial oxidative phosphorylation (OxPhos) activities are decreased in patients with fatty liver disease (Cortez-Pinto et al, 1999; Pérez-Carreras et al, 2003). Ectopic expression of peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β) promotes mitochondrial biogenesis, lipid export, fatty acid oxidation, and OxPhos (Lelliott et al, 2007; Bellafante et al, 2013)
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