• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.24 no.6
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• pp.518-527
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• 2021

Purpose: The incidence of hepatic steatosis among children has been increasing; however, data distinguishing simple steatosis from a more complex disorder are lacking. Methods: This study identified the etiologies resulting in hepatic steatosis through a retrospective review of pediatric liver biopsies performed in the last 10 years. A total of 158 patients with hepatic steatosis proven by histopathological evaluation were enrolled in the study, and baseline demographic features, anthropometric measurements, physical examination findings, laboratory data, ultrasonographic findings, and liver histopathologies were noted. Results: The two most common diagnoses were inborn errors of metabolism (IEM) (52.5%) and nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) (29.7%). The three most common diseases in the IEM group were glycogen storage disorders, Wilson's disease, and mitochondrial disease. The rates of consanguineous marriage (75.6%; odds ratio [OR], 26.040) and positive family history (26.5%; OR, 8.115) were significantly higher (p=0.002, p<0.001, respectively) in the IEM group than those in the NAFLD/NASH group. Younger age (p=0.001), normal anthropometric measurements (p=0.03), increased aspartate aminotransferase levels (p<0.001), triglyceride levels (p=0.001), and cholestatic biochemical parameters with disrupted liver function tests, as well as severe liver destruction of hepatic architecture, cholestasis, fibrosis, and nodule formation, were also common in the IEM group. Conclusion: Parents with consanguinity and positive family history, together with clinical and biochemical findings, may provide a high index of suspicion for IEM to distinguish primary steatosis from the consequence of a more complex disorder.

• Nutrition Research and Practice
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• v.14 no.6
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• pp.568-579
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• 2020

BACKGROUD/OBJECTIVES: Hepatic steatosis is the most common liver disorder, particularly in postmenopausal women. This study investigated the protective effects of standardized rice bran extract (RBS) on ovariectomized (OVX)-induced hepatic steatosis in rats. MATERIALS/METHODS: HepG2 cells were incubated with 200 µM oleic acid to induce lipid accumulation with or without RBS and γ-oryzanol. OVX rats were separated into three groups and fed a normal diet (ND) or the ND containing 17β-estradiol (E2; 10 ㎍/kg) and RBS (500 mg/kg) for 16 weeks. RESULTS: RBS supplementation improved serum triglyceride and free fatty acid levels in OVX rats. Histological analysis showed that RBS significantly attenuated hepatic fat accumulation and decreased hepatic lipid, total cholesterol, and triglyceride levels. Additionally, RBS suppressed the estrogen deficiency-induced upregulation of lipogenic genes, such as sterol regulatory element-binding protein 1 (SREBP1), acetyl-CoA carboxylase 1, fatty acid synthase, glycerol-3-phosphate acyltransferase, and stearoyl-CoA desaturase 1. CONCLUSIONS: RBS and γ-oryzanol effectively reduced lipid accumulation in a HepG2 cell hepatic steatosis model. RBS improves OVX-induced hepatic steatosis by regulating the SREBP1-mediated activation of lipogenic genes, suggesting the benefits of RBS in preventing fatty liver in postmenopausal women.

• 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.

• Natural Product Sciences
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• v.20 no.1
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• pp.65-70
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• 2014

This study was carried out to investigate the potential effects of Gardenia jasminoides (GJ) extracts, on hepatic steatosis and lipid metabolism in mice fed with high-fat diet (HFD). GJ extracts (100 mg/kg, ${\times}10$ weeks) fed mice showed reduced body weight, adipose tissue weight, reduced aminotransferase level in plasma and hepatic lipid (triglyceride, total cholesterol) content. These effects were accompanied by decreased expression of lipogenic genes, sterol regulatory element binding protein-1c (SREBP-1c), liver X receptor (LXR), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), cluster of differentiation 36 (CD36), lipoprotein lipase (LPL) and decreased lipogenic enzyme FAS and HMG-CoAR enzyme activities while elevating carnitine palmitoyltrasferase-1 (CPT) activity. Based on these results, we speculated that the inhibitory effect on hepatic steatosis of GJ extract containing geniposide is the result of suppression of lipid synthesis in mice fed with HFD, suggesting that GJ extract may be beneficial in preventing hepatic steatosis.

• The Korean Journal of Physiology and Pharmacology
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• v.22 no.1
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• pp.23-33
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• 2018

Cushing's syndrome (CS) is a collection of symptoms caused by prolonged exposure to excess cortisol. Chronically elevated glucocorticoid (GC) levels contribute to hepatic steatosis. We hypothesized that histone deacetylase inhibitors (HDACi) could attenuate hepatic steatosis through glucocorticoid receptor (GR) acetylation in experimental CS. To induce CS, we administered adrenocorticotropic hormone (ACTH; 40 ng/kg/day) to Sprague-Dawley rats by subcutaneous infusion with osmotic mini-pumps. We administered the HDACi, sodium valproate (VPA; 0.71% w/v), in the drinking water. Treatment with the HDACi decreased steatosis and the expression of lipogenic genes in the livers of CS rats. The enrichment of GR at the promoters of the lipogenic genes, such as acetyl-CoA carboxylase (Acc), fatty acid synthase (Fasn), and sterol regulatory element binding protein 1c (Srebp1c), was markedly decreased by VPA. Pan-HDACi and an HDAC class I-specific inhibitor, but not an HDAC class II a-specific inhibitor, attenuated dexamethasone (DEX)-induced lipogenesis in HepG2 cells. The transcriptional activity of Fasn was decreased by pretreatment with VPA. In addition, pretreatment with VPA decreased DEX-induced binding of GR to the glucocorticoid response element (GRE). Treatment with VPA increased the acetylation of GR in ACTH-infused rats and DEX-induced HepG2 cells. Taken together, these results indicate that HDAC inhibition attenuates hepatic steatosis through GR acetylation in experimental CS.

• Nutrition Research and Practice
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• v.14 no.4
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• pp.309-321
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• 2020

BACKGROUND/OBJECTIVES: The present study aimed to evaluate the effects of folic acid supplementation in high-fructose-induced hepatic steatosis and clarify the underlying mechanism of folic acid supplementation. MATERIALS/METHODS: Male SD rats were fed control, 64% high-fructose diet, or 64% high-fructose diet with folic acid for eight weeks. Plasma glutamate-pyruvate transaminase, glutamate-oxaloacetate transaminase, lipid profiles, hepatic lipid content, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured. RESULTS: The HF diet significantly increased hepatic total lipid and triglyceride (TG) and decreased hepatic SAM, SAH, and SAM:SAH ratio. In rats fed a high fructose diet, folic acid supplementation significantly reduced hepatic TG, increased hepatic SAM, and alleviated hepatic steatosis. Moreover, folic acid supplementation in rats fed high fructose enhanced the levels of phosphorylated AMP-activated protein kinase (AMPK) and liver kinase B (LKB1) and inhibited phosphorylation of acetyl coenzyme A carboxylase (ACC) in the liver. CONCLUSIONS: These results suggest that the protective effect of folic acid supplementation in rats fed high fructose may include the activation of LKB1/AMPK/ACC and increased SAM in the liver, which inhibit hepatic lipogenesis, thus ameliorating hepatic steatosis. The present study may provide evidence for the beneficial effects of folic acid supplementation in the treatment of non-alcoholic fatty liver disease.

• The Korean Journal of Physiology and Pharmacology
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• v.18 no.4
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• pp.333-339
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• 2014

Exendin-4 (Ex-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been known to reverse hepatic steatosis in ob/ob mice. Although many studies have evaluated molecular targets of Ex-4, its mechanism of action on hepatic steatosis and fibrosis has not fully been determined. In the liver, glucose transporter 4 (GLUT4) is mainly expressed in hepatocytes, endothelial cells and hepatic stellate cells (HSCs). In the present study, the effects of Ex-4 on GLUT4 expression were determined in the liver of ob/ob mice. Ob/ob mice were treated with Ex-4 for 10 weeks. Serum metabolic parameters, hepatic triglyceride levels, and liver tissues were evaluated for hepatic steatosis. The weights of the whole body and liver in ob/ob mice were reduced by long-term Ex-4 treatment. Serum metabolic parameters, hepatic steatosis, and hepatic fibrosis in ob/ob mice were reduced by Ex-4. Particularly, Ex-4 improved hepatic steatosis by enhancing GLUT4 via GLP-1R activation in ob/ob mice. Ex-4 treatment also inhibited hepatic fibrosis by decreasing expression of connective tissue growth factor in HSCs of ob/ob mice. Our data suggest that GLP-1 agonists exert a protective effect on hepatic steatosis and fibrosis in obesity and type 2 diabetes.

• Biomedical Science Letters
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• v.28 no.2
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• pp.101-108
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• 2022

High-fat diet (HFD)-fed ovariectomized (OVX) female mice were used as an animal model of obese postmenopausal women. We investigated the effects of ascorbic acid on the histological changes induced in the liver. Plasma alanine aminotransferase levels and liver weights were higher in mice fed an HFD for 18 weeks than in mice fed a low-fat diet, effects that were inhibited by ascorbic acid. Similarly, mice fed an ascorbic acid-supplemented HFD had less hepatic lipid accumulation than did mice fed an HFD alone. Moreover, administration of ascorbic acid reduced inflammatory cells, including mast cells and CD68-positive cells, and inflammatory foci in the liver and inhibited hepatocyte ballooning. Hepatic collagen levels were lower in ascorbic acid-treated versus non-treated mice. These results suggest that ascorbic acid inhibits hepatic steatosis, inflammation, and fibrosis in obese OVX mice. Thus, ascorbic acid intake may be useful for postmenopausal women with nonalcoholic fatty liver disease.

• The Korean Journal of Physiology and Pharmacology
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• v.23 no.6
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• pp.459-466
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• 2019

Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential.

• The Journal of Korean Medicine
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• v.38 no.2
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• pp.53-60
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• 2017

Objectives: Beakdugu-tang (BDGT) consists of three medicinal herbs, and this prescription has long been used in treatment of various digestant problem in Korea. In this study, we designed to clarify mechanisms by which Korean traditional digestive medicine, BDGT, may exert anti-hepatic steatosis effects via improved insulin resistance cell model in human hepatocellular carcinoma (HepG2) and monocyte (THP-1). Materials and methods: The preparation of BDGT and constituents were extracted with 70% ethanol. HepG2 and THP-1 were treated with different concentrations of BDGT and constituents in the presence and absence of stimulants such as free fatty acids (FFAs) and oxidized low-density lipoprotein (ox-LDL), respectively. Results: The BDGT and its constituents inhibited the FFAs-stimulated lipid accumulation in HepG2 cells. Ethanol extracts of Amomum cardamomum (ACE) improved the ox-LDL induced insulin resistance in THP-1 cells. Also, treatment of monocytic cells with ACE increased anti-hepatic steatosis related gene levels including ABCA, ABCG and SR-B1. Conclusion: The results suggest that the ethanol extract of BDGT and its constituents potently inhibit the FFAs- and ox-LDL induced liver steatosis via improved insulin resistance.