• Molecules and Cells
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• v.44 no.2
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• pp.116-125
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• 2021

Cardiovascular diseases (CVDs) are the most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) and dyslipidemia is considered at least partially responsible for the increased CVD risk in NAFLD patients. The aim of the present study is to understand how hepatic de novo lipogenesis influences hepatic cholesterol content as well as its effects on the plasma lipid levels. Hepatic lipogenesis was induced in mice by feeding a fat-free/high-sucrose (FF/HS) diet and the metabolic pathways associated with cholesterol were then analyzed. Both liver triglyceride and cholesterol contents were significantly increased in mice fed an FF/HS diet. Activation of fatty acid synthesis driven by the activation of sterol regulatory element binding protein (SREBP)-1c resulted in the increased liver triglycerides. The augmented cholesterol content in the liver could not be explained by an increased cholesterol synthesis, which was decreased by the FF/HS diet. HMG-CoA reductase protein level was decreased in mice fed an FF/HS diet. We found that the liver retained more cholesterol through a reduced excretion of bile acids, a reduced fecal cholesterol excretion, and an increased cholesterol uptake from plasma lipoproteins. Very low-density lipoproteintriglyceride and -cholesterol secretion were increased in mice fed an FF/HS diet, which led to hypertriglyceridemia and hypercholesterolemia in Ldlr-/- mice, a model that exhibits a more human like lipoprotein profile. These findings suggest that dietary cholesterol intake and cholesterol synthesis rates cannot only explain the hypercholesterolemia associated with NAFLD, and that the control of fatty acid synthesis should be considered for the management of dyslipidemia.

• Journal of Microbiology and Biotechnology
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• v.23 no.11
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• pp.1569-1576
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• 2013

In mice, supplementation of t10,c12 conjugated linoleic acid (CLA) increases liver mass and hepatic steatosis via increasing uptake of fatty acids released from adipose tissues. However, the effects of t10,c12 CLA on hepatic lipid synthesis and the associated mechanisms are largely unknown. Thus, we tested the hypothesis that gut microbiota-producing t10,c12 CLA would induce de novo lipogenesis and triglyceride (TG) synthesis in HepG2 cells, promoting lipid accumulation. It was found that treatment with t10,c12 CLA ($100{\mu}M$) for 72 h increased neutral lipid accumulation via enhanced incorporation of acetate, palmitate, oleate, and 2-deoxyglucose into TG. Furthermore, treatment with t10,c12 CLA led to increased mRNA expression and protein levels of lipogenic genes including SREBP1, ACC1, FASN, ELOVL6, GPAT1, and DGAT1, presenting potential mechanisms by which CLA may increase lipid deposition. Most strikingly, t10,c12 CLA treatment for 3 h increased phosphorylation of mTOR, S6K, and S6. Taken together, gut microbiota-producing t10,c12 CLA activates hepatic de novo lipogenesis and TG synthesis through activation of the mTOR/SREBP1 pathway, with consequent lipid accumulation in HepG2 cells.

• Nutrition Research and Practice
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• v.14 no.6
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• pp.580-592
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• 2020

BACKGROUND/OBJECTIVES: The present study aimed to further investigate the potential health beneficial effects of long-term seaweed supplementation on lipid metabolism and hepatic functions in DIO mice. MATERIALS/METHODS: Four brown seaweeds (Undaria pinnatifida [UP], Laminaria japonica [LJ], Sargassum fulvellum [SF], or Hizikia fusiforme [HF]) were added to a high fat diet (HFD) at a 5% ratio and supplemented to C57BL/6N mice for 16 weeks. Triglycerides (TGs) and total cholesterol (TC) in the liver, feces, and plasma were measured. Fecal bile acid (BA) levels in feces were monitored. Hepatic insulin signaling- and lipogenesis-related proteins were evaluated by Western blot analysis. RESULTS: Fasting blood glucose levels were significantly reduced in the LJ, SF, and HF groups compared to the HFD group by the end of 16-week feeding period. Plasma TG levels and hepatic lipid accumulation were significantly reduced in all 4 seaweed supplemented groups, whereas plasma TC levels were only suppressed in the UP and HF groups compared to the HFD group. Fecal BA levels were significantly elevated by UP, LJ, and SF supplementation compared to HFD feeding only. Lastly, regarding hepatic insulin signaling-related proteins, phosphorylation of 5'-AMP-activated protein kinase was significantly up-regulated by all 4 types of seaweed, whereas phosphorylation of protein kinase B was up-regulated only in the SF and HF groups. Lipogenesis-related proteins in the liver were effectively down-regulated by HF supplementation in DIO mice. CONCLUSIONS: Brown seaweed consumption showed hypotriglyceridemic effects in the prolonged DIO mouse model. Specifically, combinatory regulation of BA excretion and lipogenesis-related proteins in the liver by seaweed supplementation contributed to the reduction of plasma and hepatic TG levels, which inhibited hyperglycemia in DIO mice. Thus, the discrepant and species-specific functions of brown seaweeds provide novel insights for the selection of future targets for therapeutic agents.

• Development and Reproduction
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• v.27 no.2
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• pp.77-89
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• 2023

Metformin is the most widely used anti-diabetic drug that helps maintain normal blood glucose levels primarily by suppressing hepatic gluconeogenesis in type II diabetic patients. We previously found that metformin induces apoptotic death in H4IIE rat hepatocellular carcinoma cells. Despite its anti-diabetic roles, the effect of metformin on hepatic de novo lipogenesis (DNL) remains unclear. We investigated the effect of metformin on hepatic DNL and apoptotic cell death in H4IIE cells. Metformin treatment stimulated glucose consumption, lactate production, intracellular fat accumulation, and the expressions of lipogenic proteins. It also stimulated apoptosis but reduced autophagic responses. These metformin-induced changes were clearly reversed by compound C, an inhibitor of AMP-activated protein kinase (AMPK). Interestingly, metformin massively increased the production of reactive oxygen species (ROS), which was completely blocked by compound C. Metformin also stimulated the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK). Finally, inhibition of p38MAPK mimicked the effects of compound C, and suppressed the metformin-induced fat accumulation and apoptosis. Taken together, metformin stimulates dysregulated glucose metabolism, intracellular fat accumulation, and apoptosis. Our findings suggest that metformin induces excessive glucose-induced DNL, oxidative stress by ROS generation, activation of AMPK and p38MAPK, suppression of autophagy, and ultimately apoptosis.

• Journal of Nutrition and Health
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• v.30 no.2
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• pp.123-131
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• 1997

The influence of (-0-Hydroxycitrate(HCA), shown to be a competitive inhibitor of adenosine 5-triphosphate(ATP) citrate lyase, on food intake and body weight, serum triglyceride and cholosterol level, in vivo rates of fatty acid and cholesterol synthesis, and fat cell number and size was investigated. 3 groups of female, 5 weeks old Sprague Dawley rats, 8 animals each, were ad libitum meal-fed or pair-fed(3 hours from 10 : 00 to 13 : 00) AIN based high glucose diet for a total period of 8 weeks. Providing normolipidemic rats orally with 400mg of HCA formula containing approximately 20mg of HCA 1 hour prior to daily feeding schedule significantly depressed in vivo hepatic rates of fatty acid and cholesterol synthesis in the liver and adipose tissue. Serum triglyceride and cholesterol levels were significantly reduced by HCA. At the end of treatment period, the rats administered with HCA resulted in a significantly reduction in body weight gain. The reduction in weights was attributable to a significant decrease in fat cell size with a smaller extent, but not significant, reduction in fat cell number. Rats receiving HCA demonstrated less food intake than the controls ; however, this decreased caloric intake was not fully responsible for the HCA induced depression of hepatic and adipocytic lipogenesis, since experiment using pair-fed cojntrol rats showed, less magnitude but similar results. Both a anorectic and an antilipogenic properties of HCA seem to be responsible for this weight reduction activity of HCA. The outcome of this study suggest that metabolic regulation may be a feasible approach to the control of obesity and hyperlipidemia.

• Journal of Digital Convergence
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• v.17 no.8
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• pp.283-291
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• 2019

The aim of investigated the role of FABP5 in the hepatic lipogenesis and lipid metabolisms. Mice were overexpressed and silenced liver FABP5 using virus particles. Mice were fed a Western-type diet or regular chow for 1week and then sacrificed mouse after 24hr fasted. Liver homogenates were used for protein analysis by Western blot and mRNA levels by RT-PCR. Hepatic and serum lipids were analysed by thin-layer chromatography. Mice fed a Western-type or high saturated fat diet revealed large increases in FABP5 expression. However, FABP5 mRNA levels were drastically reduced under fasted. Hepatic TG was significantly increased FABP5-OEAV mice, but a significantly decreased hepatic free cholesterol under fed. The discovered a substantial decrease in hepatic TG mass with FABP5 silencing. In these data, presented evidence for an important role of FABP5 in hepatic lipogenesis and hepatic TG storage. FABP5 may also be a potential target in the treatment of NAFLD, metabolic syndrome, and obesity. Furthermore, studies to which transcription factors are involved in FABP5 expression and regulation.

• Preventive Nutrition and Food Science
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• v.3 no.4
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• pp.362-367
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• 1998

Thyroid hormone(T3) stimulates hepatic lipogenesis by increasing expression of genes, indluding acetyl-CoA carboxylase and fatty acid synthase. S14 protein, which is thougth to be involved in lipid metabolism , appears to respond in parallel . Effect of T3 on lipogenesis in white and brown adipose tissue are less clear, and may be complicated by indirect effects of the hormone. We developed an adipocytes system where the indirect effects of thyroid hormone are abolished and direct effects of T3 on lipogenesis could be tested. Fat accumulation was mesured by Oil-Red O staining. Insulin clearly enhanced fat accumulation by 2-fold . Isobutylemethylxanthie(IBMX) apeared to inhibit insulin -stimulated fat accumulation. Dexamethasone increased insulin-stimulatedfat accumulation about 1.3-fold. confluent adipocytes were cultured in serum-free medium or medium containing 10% fetal calf serum or 10% fetal calf serum stripped of thyroid hormone and lipogenesis, assessed by the incorporation of 3H2O , was measured. Medium without serum or supplemented with T3-depleted serum did not amplify the stimulatory effect of T3 on lipogenesis compared to medium containing 10% fetal calf seru. Dexamethasone alone led to a decrease inlopogenesis of about 50 % in white adipocytes and 25% in brown adipocytes. However, dexamethasone amplified the lipogenic respnse to T3 by about 30% in whit eadipocytes and 60% in brown adipocytes. T3(1$\mu$M) stimulated lipogenesis and acetyl-CoA carboxylase and fatty acid syntase mRNA levels up to 2 -fold in both types of adipocytes. It seems that these adipocytes systems are as useful model to study the effects of hormones on lipogenic gene expression as well as lipogenesis.

• Nutrition Research and Practice
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• v.7 no.4
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• pp.294-301
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• 2013

In this study, we examined the hepatic anti-steatosis activity of carnosic acid (CA), a phenolic compound of rosemary (Rosmarinus officinalis) leaves, as well as its possible mechanism of action, in a high-fat diet (HFD)-fed mice model. Mice were fed a HFD, or a HFD supplemented with 0.01% (w/w) CA or 0.02% (w/w) CA, for a period of 12 weeks, after which changes in body weight, blood lipid profiles, and fatty acid mechanism markers were evaluated. The 0.02% (w/w) CA diet resulted in a marked decline in steatosis grade, as well as in homeostasis model assessment of insulin resistance (HOMA-IR) index values, intraperitoneal glucose tolerance test (IGTT) results, body weight gain, liver weight, and blood lipid levels (P < 0.05). The expression level of hepatic lipogenic genes, such as sterol regulating element binding protein-1c (SREBP-1c), liver-fatty acid binding protein (L-FABP), stearoyl-CoA desaturase 1 (SCD1), and fatty acid synthase (FAS), was significantly lower in mice fed 0.01% (w/w) CA and 0.02% (w/w) CA diets than that in the HFD group; on the other hand, the expression level of ${\beta}$-oxidation-related genes, such as peroxisome proliferator-activated receptor ${\alpha}$ (PPAR-${\alpha}$), carnitine palmitoyltransferase 1 (CPT-1), and acyl-CoA oxidase (ACO), was higher in mice fed a 0.02% (w/w) CA diet, than that in the HFD group (P < 0.05). In addition, the hepatic content of palmitic acid (C16:0), palmitoleic acid (C16:1), and oleic acid (C18:1) was significantly lower in mice fed the 0.02% (w/w) CA diet than that in the HFD group (P < 0.05). These results suggest that orally administered CA suppressed HFD-induced hepatic steatosis and fatty liver-related metabolic disorders through decrease of de novo lipogenesis and fatty acid elongation and increase of fatty acid ${\beta}$-oxidation in mice.

• BMB Reports
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• v.49 no.2
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• pp.105-110
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• 2016

Ursodeoxycholic acid (UDCA), a natural, hydrophilic nontoxic bile acid, is clinically effective for treating cholestatic and chronic liver diseases. We investigated the chronic effects of UDCA on age-related lipid homeostasis and underlying molecular mechanisms. Twenty-week-old C57BL/6 male and female mice were fed a diet with or without 0.3% UDCA supplementation for 25 weeks. UDCA significantly reduced weight gain, adiposity, hepatic triglyceride, and hepatic cholesterol without incidental hepatic injury. UDCA-mediated hepatic triglyceride reduction was associated with downregulated hepatic expression of peroxisome proliferator-activated receptor-γ, and of other genes involved in lipogenesis (Chrebp, Acaca, Fasn, Scd1, and Me1) and fatty acid uptake (Ldlr, Cd36). The inflammatory cytokines Tnfa, Ccl2, and Il6 were significantly decreased in liver and/or white adipose tissues of UDCA-fed mice. These data suggest that UDCA exerts beneficial effects on age-related metabolic disorders by lowering the hepatic lipid accumulation, while concurrently reducing hepatocyte and adipocyte susceptibility to inflammatory stimuli.

• Journal of Nutrition and Health
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• v.40 no.8
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• pp.693-700
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• 2007

This study was performed to investigate the effects of genistein, a kind of soy isoflavones, on fatty liver and lipid metabolism in rats fed high fat diet. Twenty four male Sprague-Dawley rats were divided into four groups by dietary fat and genistein contents then raised for six weeks. The rats(n=6/group) were fed normal fat diet(NOR), high fat diet (HF), high fat with 0.1% genistein(HF+0.1%G) or high fat with 0.2% genistein(HF+0.2%G). Hepatic total lipid, triglyceride, total cholesterol and Serum GPT, as a marker for fatty liver, were significantly increased by high fat diet. Also, serum total lipid, triglyceride, total cholesterol, glucose and insulin concentration, hepatic lipogenic enzyme (fatty acid synthase and malic enzyme) activities were significantly increased by high fat diet. However, hepatic total lipid, triglyceride, total cholesterol and Serum GPT were significantly decreased by genistein intake. Also, genistein supplementation decreased serum total lipid, triglyceride, glucose and insulin concentration, hepatic lipogenic enzyme (fatty acid synthase and malic enzyme) activities. There were no differences by genistein level except for serum insulin. These results suggest that fatty liver induced by high fat diet was caused by increased serum lipid profiles and hepatic lipogenesis, whereas, genistein may be useful in inhibiting of fatty liver by reducing serum lipid profiles and hepatic lipogenesis.