Medaka as a model for human nonalcoholic steatohepatitis

Abstract

SUMMARY The global incidence of nonalcoholic steatohepatitis (NASH) is increasing and current mammalian models of NASH are imperfect. We have developed a NASH model in the ricefish medaka (Oryzias latipes), which is based on feeding the fish a high-fat diet (HFD). Medaka that are fed a HFD (HFD-medaka) exhibited hyperlipidemia and hyperglycemia, and histological examination of the liver revealed ballooning degeneration. The expression of lipogenic genes (SREBP-1c, FAS and ACC1) was increased, whereas the expression of lipolytic genes (PPARA and CPT1) was decreased. With respect to liver fatty acid composition, the concentrations of n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs had declined and the n-3:n-6 ratio was reduced. Treatment of HFD-medaka with the n-3 PUFA eicosapentaenoic acid (EPA) mitigated disease, as judged by the restoration of normal liver fatty acid composition and normal expression levels of lipogenic and lipolytic genes. Moreover, medaka that were fed a diet deficient in n-3 PUFAs developed NASH features. Thus, NASH can be induced in medaka by a HFD, and the proportion of n-3 PUFAs in the liver influences the progress of NASH pathology in these fish. Our model should prove helpful for the dissection of the causes of human NASH and for the design of new and effective therapies.

The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model

“…Several studies have demonstrated that EPA treatment can increase mitochondrial and peroxisomal fatty acid oxidations. In particular, a recent NASH model using Medaka revealed that the administration of EPA mitigated high fat diet-induced disease by restoring normal mitochondrial β-oxidation (Matsumoto et al, 2010), which is confirmed by our findings. Therefore, we conclude that the EPA-mediated reduction of hepatic TG accumulation and attenuation of macrovesicular steatosis at 8 weeks may be attributed to the enhanced mitochondrial and peroxisomal β-oxidations.…”

“…However, according to the proposed pathways for major lipid metabolism (Zhou et al, 2008), the decreased levels of SCD1 and DGAT2 in the HFC diet-fed group might be indicative of mitochondrial dysfunction. Several animal experiments have demonstrated that the administration of EPA improved hepatic steatosis by inhibiting mRNA (Ishii et al, 2009;Kajikawa et al, 2009a,b;Matsumoto et al, 2010) or protein (Tanaka et al, 2010) levels of SREBP-1c and lipogenic enzymes. Although we observed a marked down-regulation of these enzymes at the mRNA level, we failed to observe a significant role for EPA at the protein level.…”

Antihypercholesterolemic Effects of Mushroom, Chrysin, Curcumin and Omega-3 in Experimental Hypercholesterolemic Rats

“…The lipid-lowering effect of omega-3 in liver is not solely due to acceleration of fatty acid oxidation by PPAR-α activation but due to its effect on other signaling pathways. Moreover, omega-3 regulated the expression of SREBP-1c and FAS ( Figure 4A-B) as supported by other studies [63,64]. The decrease in apoCIII expression is due to the upregulation in PPAR-α expression, thus contributing to the lipid and lipoprotein lowering properties of fish or fish oil intake [65].…”

Evaluation of the effects of L-carnitine on medaka (Oryzias latipes) fatty liver

“…Blood samples were collected as described 8 . Fish were kept on ice for 1–2 minutes and then bled by cutting a ventral portion of the tail fin.…”

“…It has previously been reported that drug assessment using a HFD-fed medaka model is feasible 8 . However, no studies of the effects of L-carnitine on fatty liver found in this model have been reported.…”