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A high-fat diet may result in changes in hepatic clock gene expression, but potential mechanisms are not yet elucidated. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine protein kinase that is recognized as a key regulator of energy metabolism and certain clock genes. Therefore, we hypothesized that AMPK may be involved in the alteration of hepatic clock gene expression under a high-fat environment. This study aimed to examine the effects of timed high-fat evening diet on the activity of hepatic AMPK, clock genes, and lipogenic genes. Mice with hyperlipidemic fatty livers were induced by orally administering high-fat milk via gavage every evening (19:00-20:00) for 6 weeks. Results showed that timed high-fat diet in the evening not only decreased the hepatic AMPK protein expression and activity but also disturbed its circadian rhythm. Accordingly, the hepatic clock genes, including clock, brain-muscle-Arnt-like 1, cryptochrome 2, and period 2, exhibited prominent changes in their expression rhythms and/or amplitudes. The diurnal rhythms of the messenger RNA expression of peroxisome proliferator-activated receptorα, acetyl-CoA carboxylase 1α, and carnitine palmitoyltransferase 1 were also disrupted; the amplitude of peroxisome proliferator-activated receptorγcoactivator 1α was significantly decreased at 3 time points, and fatty liver was observed. These findings demonstrate that timed high-fat diet at night can change hepatic AMPK protein levels, activity, and circadian rhythm, which may subsequently alter the circadian expression of several hepatic clock genes and finally result in the disorder of hepatic lipogenic gene expression and the formation of fatty liver., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Some polyphenols derived from plants may ameliorate hyperlipidemic fatty livers; therefore, we hypothesized that polyphenol-rich Chrysanthemum morifolium extract (CME) may exert an inhibitory effect on the formation of hyperlipidemic fatty livers in mice. This study aimed to examine the effects of CME on lipids in blood and liver and on peroxisome proliferator-activated receptor (PPAR)α-mediated gene expression. Mice with hyperlipidemic fatty livers induced by orally administering high-fat milk via gavage and being simultaneously treated with 75 to 300 mg/kg CME for 6 weeks. After CME addition, the serum total cholesterol levels and hepatic weight coefficients decreased, but no significant reduction in the serum triacylglycerol levels were observed. It is important to note that CME might decrease hepatic lipid accumulation, sterol regulatory element binding protein-1c, and fatty acid synthase expression and increase hepatic PPARα, lipoprotein lipase, and cholesterol 7α-hydroxylase expression. However, the expected reduction in hepatic diacylglycerol acyltransferase mRNA expression was not observed. These findings demonstrate that polyphenol-rich CME may prevent hyperlipidemic fatty liver in mice, and its mechanisms may be related to the modulation of sterol regulatory element binding protein-1c, FAS, lipoprotein lipase, and cholesterol 7α-hydroxylase 1 expression through the PPARα-mediated pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The objectives of this study were to determine the effect of osthole on the insulin resistance (IR) in high-fat and high-sucrose-induced fatty liver rats and to investigate its potential mechanisms. The rat model was established by orally feeding high-fat and high-sucrose emulsion by gavage for 9 weeks. The experimental rats were treated with osthole 5 and 10 mg/kg, lipanthyl 30 mg/kg, and rosiglitazone 4 mg/kg after oral high-fat and high-sucrose emulsion for 6 weeks and were sacrificed 4 weeks after administration. The total cholesterol (TC), triglycerides (TG), and free fatty acids (FFA) in serum and hepatic tissue, fasting blood glucose (FBG), fasting serum insulin (FINS), serum adiponectin, and liver weight were measured. The homeostasis model assessment of insulin resistance (HOMA-IR) and coefficient of hepatic weight were calculated. The results showed that after treatment with osthole, the serum levels of TC, TG, and FFA, the contents of TG and FFA in hepatic tissue, and body weight gain were lowered, especially in the osthole 10 mg/kg group (p < 0.05 or p < 0.01). Moreover, the histological evaluation of liver specimens demonstrated that the steatosis and inflammation in liver in osthole-treated groups were improved, especially in the 10 mg/kg group (p < 0.05). Importantly, the levels of FBG, FINS, and HOMA-IR in the osthole 10 mg/kg group were decreased (p < 0.01), while the level of serum adiponectin in the osthole-treated groups, like PPAR α agonist lipanthyl and PPAR γ agonist rosiglitazone, was increased (p < 0.05). These results revealed that osthole could improve the IR induced by high-fat and high-sucrose emulsion in fatty liver rats, and its mechanism might be associated with increment of adiponectin release via activation of PPAR α/ γ pathway., (© Georg Thieme Verlag KG Stuttgart · New York.)

The objectives of this study were to determine the therapeutic effect of osthole, an active constituent isolated from Cnidium monnieri (L.) Cusson (Apiaceae), in hyperlipidemic fatty liver (HFL) rats and investigate the possible mechanism of the osthole treatment. The HFL rat model was established by feeding Sprague-Dawley rats with fat milk for 6 weeks. The experimental rats were then treated with a dose of osthole of 5 - 20 mg/kg for 6 weeks. After the treatment, total cholesterol (TC) and triglycerides (TG) in serum and hepatic tissue, as well as the coefficient of hepatic weight were measured. The results showed that the TC and TG in both serum and hepatic tissue and the coefficient of hepatic weight in the osthole-treated rats were lower as compared to those in the experimental group, respectively (P < 0.05 or P < 0.01). Moreover, as compared to the control group, the osthole treatment increased the PPARalpha/gamma mRNA expression by 58.0 - 84.0 % and 20.4 - 77.4 %, respectively. The related target genes for mRNA expression were also increased by osthole-treatment, e. g., 53.4 - 93.2 % for CYP7A, 21.1 - 63.2 % for L-FABP and 34.1 - 57.3 % for FATP4, while the DGAT mRNA expression was decreased by 26.0 - 44.4 %. The therapeutic effect of osthole was further confirmed by histological evaluation of the liver showing a dramatically decreased lipid accumulation and improved ultrastructure of hepatocytes. In conclusion, osthole exerts therapeutic effects on fat milk-induced fatty liver in rats, by regulating mRNA expression of the target genes of CYP7A, DGAT, L-FABP and FATP4 via increasing the PPARalpha/gamma mRNA expression.