Models of non-Alcoholic Fatty Liver Disease and Potential Translational Value: the Effects of 3,5-L-diiodothyronine

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in industrialized countries and is associated with increased risk of cardiovascular, hepatic and metabolic diseases. Molecular mechanisms on the root of the disrupted lipid homeostasis in NAFLD and potential therapeutic strategies can benefit of in vivo and in vitro experimental models of fatty liver. Here, we describe the high fat diet (HFD)-fed rat in vivo model, and two in vitro models, the primary cultured rat fatty hepatocytes or the FaO rat hepatoma fatty cells, mimicking human NAFLD. Liver steatosis was invariably associated with increased number/size of lipid droplets (LDs) and modulation of expression of genes coding for key genes of lipid metabolism such as peroxisome proliferator-activated receptors (Ppars) and perilipins (Plins). In these models, we tested the anti-steatotic effects of 3,5-L-diiodothyronine (T2), a metabolite of thyroid hormones. T2 markedly reduced triglyceride content and LD size acting on mRNA expression of both Ppars and Plins. T2 also stimulated mitochondrial oxidative metabolism of fatty acids. We conclude that in vivo and especially in vitro models of NAFLD are valuable tools to screen a large number of compounds counteracting the deleterious effect of liver steatosis. Because of the high and negative impact of liver steatosis on human health, ongoing experimental studies from our group are unravelling the ultimate translational value of such cellular models of NAFLD.

Dysregulation of Bile Acids in Patients with NAFLD

“…Several rodent models for NAFLD have been developed [113][114][115], including high-fat cholesterol (HFC) and methionine-and choline-deficient (MCD) diet-induced or genetic deficient models, including leptin-deficient ob/ob, leptin receptor-deficient db/db mice, and fa/fa rats. Several preclinical studies were conducted to investigate the effects of NAFLD on bile acid homeostasis using NAFLD mouse or rat models.…”

A UPLC-MS/MS method for simultaneous quantification of pairs of oleanene- and ursane-type triterpenoid saponins and their major metabolites in mice plasma and its application to a comparative pharmacokinetic study

“…It was widely used in experimental animals to model human NAFLD. 20 As previously described, [21][22][23] in the model of NAFLD high-fat diet feeding induced body weight and liver weight, increased epididymal and perirenal fat accumulation (Table 4). Moreover, mice fed with high-fat diet showed signicantly higher plasma total cholesterol and AST, ALT levels in comparison with control mice (+58%, +465%, +83%, respectively, vs. control) ( Table 4).…”

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

“…Notably, treatment of steatotic FaO cells with 3,5-T2 or T3 for 24 h reduced TAG content as well as the number and size of LDs. The effects of 3,5-T2 were also accompanied by a reduction of PPARγ [282,283]. These findings demonstrated that the direct hypolipidizing effect exerted both by 3,5-T2 and T3 on the hepatic cells can occur even in the absence of TRs [264,265,282] and are based on the ability to activate pathways affecting TAG deposits within LDs and to promote mitochondrial oxidation and/or exocytosis of the very low density lipoproteins (VLDL) [284].…”

“…The effects of 3,5-T2 were also accompanied by a reduction of PPARγ [282,283]. These findings demonstrated that the direct hypolipidizing effect exerted both by 3,5-T2 and T3 on the hepatic cells can occur even in the absence of TRs [264,265,282] and are based on the ability to activate pathways affecting TAG deposits within LDs and to promote mitochondrial oxidation and/or exocytosis of the very low density lipoproteins (VLDL) [284]. The 3,5-T2-mediated effects in steatotic hepatocytes in culture also include the recruitment to LDs of the adipose triglyceride lipase (ATGL), which might be an early mediator of iodothyronine action [282,285].…”

“…Furthermore, PPAR β/δ play a crucial role in hepatic lipid homeostasis and insulin sensitivity, by activating glycolysis and lipogenesis [280]. The relative concentrations of the different PPARs change depending on both physiologic and pathological conditions [281]; moreover, specific lipid mixtures used to feed both the animals and the isolated cells can have a significant impact on the dynamic equilibrium of PPAR regulation [264,282]. All the PPAR subtypes (PPARα, PPARγ, and PPARδ) are constitutively expressed in FaO rat hepatoma cells [275,276].…”