Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD), a metabolic predisposition for development of hepatocellular carcinoma (HCC), represents a disease spectrum ranging from steatosis to steatohepatitis to cirrhosis. Acox1, a rate-limiting enzyme in peroxisomal fatty acid β-oxidation, regulates metabolism, spontaneous hepatic steatosis, and hepatocellular damage over time. However, it is unknown whether Acox1 modulates inflammation relevant to NAFLD pathogenesis or if Acox1-associated metabolic and inflammatory derangements uncover and accelerate potential for NAFLD progression. Here, we show that mice with a point mutation in Acox1 (Acox1Lampe1) exhibited altered cellular metabolism, modified T cell polarization, and exacerbated immune cell inflammatory potential. Further, in context of a brief obesogenic diet stress, NAFLD progression associated with Acox1 mutation resulted in significantly accelerated and exacerbated hepatocellular damage via induction of profound histological changes in hepatocytes, hepatic inflammation, and robust upregulation of gene expression associated with HCC development. Collectively, these data demonstrate that β-oxidation links metabolism and immune responsiveness and that a better understanding of peroxisomal β-oxidation may allow for discovery of mechanisms central for NAFLD progression.

Dysregulation of Lipid Metabolism in Mkp-1 Deficient Mice during Gram-Negative Sepsis

“…We also assessed the expression of genes involved in fatty acid β-oxidation through qRT-PCR (Figure 10A). Carnitine palmitoyltransferase I and II (Cpt1a and Cpt2) are essential enzymes for β-oxidation of long chain fatty acid in mitochondria [39,40], while acyl-CoA oxidase 1 (Acox1) mediates fatty acid β-oxidation in peroxisome [39,41]. Cpt1a mRNA expression was significantly decreased in both Mkp-1 +/+ and Mkp-1 −/− mice upon E. coli infection, although expression levels in control conditions were similar in the two genotypes of mice.…”

“…Fatty acids taken up from the blood can be converted in the liver to triglyceride by Dgat2 [56]. We think that the liver likely synthesizes triglyceride for consumption by other organs, because both the mitochondrial fatty acid β-oxidation-related Cpt1a protein [39,40]) and peroxisomal fatty acid β-oxidation protein Acox1 [39,41,57] are downregulated in Mkp-1 +/+ mice after E. coli infection (Figure 10). It is worth noting that a recent study has shown that p38 inhibition enhanced parenteral nutrition-induced hepatic steatosis and attenuated the expression of Cpt1a, Acox1, and Ppargc1a in a rat model [58].…”

PPARα agonist and metformin co-treatment ameliorates NASH in mice induced by a choline-deficient, amino acid-defined diet with 45% fat

“…The major mechanism driving hepatic TG accumulation is increased delivery of free fatty acids from peripheral adipose depots to the liver. Hepatic lipid disposal via mitochondrial/ peroxisomal β-oxidation and lipoprotein export are central mechanisms that function to eliminate potentially toxic free fatty acids 35,36,38 . To investigate why liver steatosis was ameliorated by GW7647 monotherapy and co-treatment, we assessed hepatic mitochondrial and peroxisomal β-oxidation-related gene expression of CPT1, 2, and ACOX1 by real-time PCR.…”

Metallothionein 3 Controls the Phenotype and Metabolic Programming of Alternatively Activated Macrophages

“…Analysis of mitochondrial function by Seahorse technology was performed as reported before with slight modifications (Gandhi et al, 2015; Moreno-Fernandez et al, 2018). Specifically, to assess baseline OCR, 10 5 Mϕ were plated in XF24 cell culture microplates (Seahorse Biosciences) and transfected with scramble or Mt3 siRNA for 5h in RPMI media as described above.…”