Dietary carnosic acid suppresses hepatic steatosis formation via regulation of hepatic fatty acid metabolism in high-fat diet-fed mice

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 β-oxidation-related genes, such as peroxisome proliferator-activated receptor α (PPAR-α), 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 β-oxidation in mice.     

氧化应激在亚慢性氟中毒大鼠肝脏损伤中的作用

目的 探讨氧化应激在亚慢性氟中毒大鼠肝脏损伤中的作用。方法 在饮水中加入50，100，和150mg／L氟化钠(NaF)喂饲大鼠3个月，制备亚慢性氟中毒模型。测定染氟各组大鼠肝脏脂质过氧化产物丙二醛(MDA)的含量及抗氧化酶超氧化物歧化酶(S0D)、谷胱甘肽过氧化物酶(GSH—Px)的活力，同时检测血清中谷丙转氨酶(SG-PT)、谷草转氨酶(SGOT)的活性。结果 150mg/L染氟组大鼠肝脏MDA含量显高于对照组(P＜0．01)；100，150mg／L染氟组大鼠肝脏S0D活力显下降(P＜0．05)；随染氟剂量增加，GSH—PX活力有下降趋势；150mg／L染氟组SGPT活性显高于对照组(P＜0．01)，100，150mg/L染氟组SGOT活性显高于对照组(P＜0．01)，MDA与SGPT之间存在显正相关(r＝0．460，P＝0．007)。结论 氟中毒大鼠肝脏内氧化系统与抗氧化系统失衡，氧化应激引起的氧化损伤作用可能是氟致大鼠肝毒性的重要原因之一。     

Association between Mediterranean Diet and Fatty Liver in Women with Overweight and Obesity

Obesity is a risk factor for NAFLD. However, not all people with obesity have an excessive intrahepatic fat content. Adherence to a high-quality dietary pattern may also promote liver health in obesity. A cross-sectional study of 2967 women with overweight and obesity was carried out to assess the association between a Mediterranean diet and fatty liver. All women underwent clinical examination, anthropometric measurements, blood sampling, ultrasound measurements of abdominal visceral and subcutaneous fat, and assessment of adherence to the Mediterranean diet using the 14-item MEDAS questionnaire. Fatty liver index (FLI), NAFLD fatty liver steatosis (NAFLD-FLS) and hepatic steatosis index (HSI) were calculated. In women with obesity, the MEDAS score was inversely associated with FLI (β = −0.60, 95% CI: −1.04, −0.16, p = 0.008), NAFLD-FLS (β = −0.092, 95% CI: −0.134, −0.049, p < 0.001) and HSI (β = −0.17, 95% CI: −0.30, −0.04, p = 0.011). Stronger associations were observed in premenopausal women with obesity. Mediterranean diet was inversely associated with NAFLD-FLS in women with overweight, independently of menopausal status. In conclusion, Mediterranean diet is associated with a better liver status in women with overweight and obesity. This may have a public health impact and be useful in drafting nutritional guidelines for NAFLD.     

Green perilla leaf extract ameliorates long-term oxidative stress induced by a high-fat diet in aging mice

BACKGROUND/OBJECTIVESOxidative stress is caused by an imbalance between harmful free radicals and antioxidants. Long-term oxidative stress can lead to an “exhausted” status of antioxidant defense system triggering development of metabolic syndrome and chronic inflammation. Green perilla (Perilla frutescens) is commonly used in Asian cuisines and traditional medicine in southeast Asia. Green perilla possesses numerous beneficial effects including anti-inflammatory and antioxidant functions. To investigate the potentials of green perilla leaf extract (PE) on oxidative stress, we induced oxidative stress by high-fat diet (HFD) in aging mice.MATERIALS/METHODSC57BL/6J male mice were fed HFD continuously for 53 weeks. Then, mice were divided into three groups for 12 weeks: a normal diet fed reference group (NDcon), high-fat diet fed group (HDcon), and high-fat diet PE treated group (HDPE, 400 mg/kg of body weight). Biochemical analyses of serum and liver tissues were performed to assess metabolic and inflammatory damage and oxidative status. Hepatic gene expression of oxidative stress and inflammation related enzymes were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR).RESULTSPE improved hepatopathology. PE also improved the lipid profiles and antioxidant enzymes, including hepatic glutathione peroxidase (GPx) and superoxide dismutase (SOD) and catalase (CAT) in serum and liver. Hepatic gene expressions of antioxidant and anti-inflammatory related enzymes, such as SOD-1, CAT, interleukin 4 (IL-4) and nuclear factor erythroid 2-related factor (Nrf2) were significantly enhanced by PE. PE also reduced the levels of hydrogen peroxide (H₂O₂) and malondialdehyde (MDA) in the serum and liver; moreover, PE suppressed hepatic gene expression involved in pro-inflammatory response; Cyclooxygenase-2 (COX-2), nitric oxide synthase (NOS), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6).CONCLUSIONSThis research opens opportunities for further investigations of PE as a functional food and possible anti-aging agent due to its attenuative effects against oxidative stress, resulting from HFD and aging in the future.     

Long term effects of high fat and sucrose diets on obesity and lymphocyte proliferation in mice

Objective  To clarify the effect of prolonged feeding of a high-fat and sucrose, and to clarify the effect of sucrose instead of other carbohydrate on obesity and immunity in C57BL/6J mice. Methods  We investigated the development of obesity and immune cell function in four groups of mice fed high-fat, high-fat plus high-sucrose, high-sucrose, and control diet for 7 months. Results  Mice fed high-fat and high-fat plus high-sucrose groups developed severe obesity. Body weight, adipose tissue weight, serum leptin, blood glucose, and insulin were significantly higher, while the level of serum soluble leptin receptor was significantly lower in mice fed high-fat and high-fat plus high-sucrose diets than in mice fed the control or high-sucrose diets. Splenocyte proliferation stimulated by T-cell mitogen (PHA, ConA, and anti-CD 3 antibody) and B-cell mitogen (LPS) was significantly lower in both obese, high-fat and high-fat plus high-sucrose groups than in control and high-sucrose groups. However, these parameters did not differ between high-fat and high-fat plus high-sucrose groups. Conclusions  Long-term feeding of high-fat diet and high-fat plus high-sucrose diet similarly induced severe obesity in C57BL/6J mice. Not only T-cell, but also B-cell function may be impaired in mice made severely obese by the high-fat or high-fat plus high-sucrose diets.     

Medium-chain fatty acid reduces lipid accumulation by regulating expression of lipid-sensing genes in human liver cells with steatosis

Accumulation of lipids in the liver can lead to cell dysfunction and steatosis, an important factor in pathogenesis causing non-alcoholic fatty liver disease. The mechanisms related to lipid deposition in the liver, however, remain poorly understood. This study was aimed to investigate the effects of medium-chain fatty acid (MCFA) on the lipolysis and expression of lipid-sensing genes in human liver cells with steatosis. A cellular steatosis model, which is suitable to experimentally investigate the impact of fat accumulation in the liver, was established in human normal liver cells (LO2 cells) with a mixture of free fatty acids (oleate/palmitate, 2:1) at 200?μm for 24?h incubation. MCFA was found to down-regulate expression of liver X receptor-α, sterol regulatory element binding protein-1, acetyl-CoA carboxylase, fatty acid synthase, CD 36 and lipoprotein lipase in this cellular model, and have positive effects on adipose triglyceride lipase and hormone-sensitive lipase. These results suggest that MCFA may reduce lipid accumulation by regulating key lipid-sensing genes in human liver cells with steatosis.     

Amelioration of Hepatic Steatosis in Mice through Bacteroides uniformis CBA7346-Mediated Regulation of High-Fat Diet-Induced Insulin Resistance and Lipogenesis

Dietary habits and gut microbiota play an essential role in non-alcoholic fatty liver disease (NAFLD) and related factors such as insulin resistance and de novo lipogenesis. In this study, we investigated the protective effects of Bacteroides uniformis CBA7346, isolated from the gut of healthy Koreans, on mice with high-fat diet (HFD)-induced NAFLD. Administration of B. uniformis CBA7346 reduced body and liver weight gain, serum alanine aminotransferase and aspartate aminotransferase levels, liver steatosis, and liver triglyceride levels in mice on an HFD; the strain also decreased homeostatic model assessment for insulin resistance values, as well as serum cholesterol, triglyceride, lipopolysaccharide, leptin, and adiponectin levels in mice on an HFD. Moreover, B. uniformis CBA7346 controlled fatty liver disease by attenuating steatosis and inflammation and regulating de novo lipogenesis-related proteins in mice on an HFD. Taken together, these findings suggest that B. uniformis CBA7346 ameliorates HFD-induced NAFLD by reducing insulin resistance and regulating de novo lipogenesis in obese mice.     

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

Many studies have shown that resveratrol has a lot of therapeutic effects on liver disorders. Its administration can significantly increase the survival rate after liver transplantation, reduce fat deposition and ischemia-induced necrosis and apoptosis in Wistar rats. Resveratrol can provide Liver protection against chemical, cholestatic, and alcohol-mediated damage. It can improve glucose metabolism and lipid profile, reduce liver fibrosis, and steatosis. Additionally, it is capable of altering the fatty acid composition of the liver cells. Resveratrol may be a potential treatment option for the management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant, and calorie-restricting effects. There are also studies that have evaluated the effect of resveratrol on lipid and liver enzyme profiles among patients with metabolic syndrome (MetS) and related disorders. Based on the extent of liver disease worldwide and the need to find new treatment possibilities, this review critically examines current in vitro and in vivo preclinical studies and human clinical studies related to liver protection.     

Effects of excessive dietary methionine on oxidative stress and dyslipidemia in chronic ethanol-treated rats

BACKGROUND/OBJECTIVE

The aim of this study was to examine the effect of high dietary methionine (Met) consumption on plasma and hepatic oxidative stress and dyslipidemia in chronic ethanol fed rats.

MATERIALS/METHODS

Male Wistar rats were fed control or ethanol-containing liquid diets supplemented without (E group) or with DL-Met at 0.6% (EM1 group) or 0.8% (EM2 group) for five weeks. Plasma aminothiols, lipids, malondialdehyde (MDA), alanine aminotransferase (ALT), and aspartate aminotransferase were measured. Hepatic folate, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured.

RESULTS

DL-Met supplementation was found to increase plasma levels of homocysteine (Hcy), triglyceride (TG), total cholesterol (TC), and MDA compared to rats fed ethanol alone and decrease plasma ALT. However, DL-Met supplementation did not significantly change plasma levels of HDL-cholesterol, cysteine, cysteinylglycine, and glutathione. In addition, DL-Met supplementation increased hepatic levels of folate, SAM, SAH, and SAM:SAH ratio. Our data showed that DL-Met supplementation can increase plasma oxidative stress and atherogenic effects by elevating plasma Hcy, TG, and TC in ethanol-fed rats.

CONCLUSION

The present results demonstrate that Met supplementation increases plasma oxidative stress and atherogenic effects by inducing dyslipidemia and hyperhomocysteinemia in ethanol-fed rats.     

Docosahexaenoic acid and arachidonic acid prevent essential fatty acid deficiency and hepatic steatosis

Objectives: Essential fatty acids are important for growth, development, and physiologic function. α‐Linolenic acid and linoleic acid are the precursors of docosahexaenoic and arachidonic acid, respectively, and have traditionally been considered the essential fatty acids. However, the authors hypothesized that docosahexaenoic acid and arachidonic acid can function as the essential fatty acids. Methods: Using a murine model of essential fatty acid deficiency and consequent hepatic steatosis, the authors provided mice with varying amounts of docosahexaenoic and arachidonic acids to determine whether exclusive supplementation of docosahexaenoic and arachidonic acids could prevent essential fatty acid deficiency and inhibit or attenuate hepatic steatosis. Results: Mice supplemented with docosahexaenoic and arachidonic acids at 2.1% or 4.2% of their calories for 19 days had normal liver histology and no biochemical evidence of essential fatty acid deficiency, which persisted when observed after 9 weeks. Conclusion: Supplementation of sufficient amounts of docosahexaenoic and arachidonic acids alone without α‐linolenic and linoleic acids meets essential fatty acid requirements and prevents hepatic steatosis in a murine model.     

Effects of Dietary Fat and Saturated Fat Content on Liver Fat and Markers of Oxidative Stress in Overweight/Obese Men and Women under Weight-Stable Conditions

Dietary fat and oxidative stress are hypothesized to contribute to non-alcoholic fatty liver disease and progression to steatohepatitis. To determine the effects of dietary fat content on hepatic triglyceride, body fat distribution and markers of inflammation and oxidative stress, overweight/obese subjects with normal glucose tolerance consumed a control diet (CONT: 35% fat/12% saturated fat/47% carbohydrate) for ten days, followed by four weeks on a low fat (LFD (n = 10): 20% fat/8% saturated fat/62% carbohydrate) or high fat diet (HFD (n = 10): 55% fat/25% saturated fat/27% carbohydrate). Hepatic triglyceride content was quantified by MRS and abdominal fat distribution by MRI. Fasting biomarkers of inflammation (plasma hsCRP, IL-6, IL-12, TNFα, IFN-γ) and oxidative stress (urinary F2-α isoprostanes) were measured. Body weight remained stable. Compared to the CONT, hepatic triglyceride decreased on the LFD (mean (95% CI): change −2.13% (−3.74%, −0.52%)), but did not change on the HFD and there was no significant difference between the LFD and HFD. Intra-abdominal fat did not change significantly on either diet, but subcutaneous abdominal fat increased on the HFD. There were no significant changes in fasting metabolic markers, inflammatory markers and urinary F2-α isoprostanes. We conclude that in otherwise healthy overweight/obese adults under weight-neutral conditions, a diet low in fat and saturated fat has modest effects to decrease liver fat and may be beneficial. On the other hand, a diet very high in fat and saturated fat had no effect on hepatic triglyceride or markers of metabolism, inflammation and oxidative stress.     

硫辛酸对高脂饲料小鼠氧化应激与糖、脂代谢基因表达的影响

目的探讨硫辛酸(LA)对高脂饲料小鼠血糖、血脂代谢和抗氧化能力的影响。方法24只C57BL/6雄性小鼠,随机分为3组:即对照组(正常饲料),高脂组(高脂饲料),LA组(高脂饲料+0.1%LA),6周后测定空腹血糖(FPG)、胰岛素(FINS)、甘油三酯(TG)、总胆固醇(TC)等糖脂代谢指标以及丙二醛(MDA)、超氧化物歧化酶(SOD)和总抗氧化能力(TAC)等抗氧化指标,同时用Affymetrix MOE430A基因芯片分析肝脏抗氧化、糖脂代谢相关功能基因的表达。结果与高脂组相比,LA组MDA含量显著降低,TAC明显升高(P<0.05)。LA显著降低血浆TG、TC、LDL-C和FPG、FINS的水平(P<0.05),MDA含量与HDL-C/TC(r=-0.47,P<0.05)和胰岛素抵抗指数(r=0.74,P<0.05)显著相关。硫辛酸改变高脂组自由基/氧化应激、糖脂代谢相关通路大部分响应基因的表达水平。结论高脂引发氧化-抗氧化系统失衡,硫辛酸通过直接清除自由基以及恢复自由基/氧化应激通路相关基因的表达水平解除氧化应激而有助于防治高脂引发的糖脂代谢紊乱。     

Lipoic Acid Exacerbates Oxidative Stress and Lipid Accumulation in the Liver of Wistar Rats Fed a Hypercaloric Choline-Deficient Diet

Non-alcoholic fatty liver disease (NAFLD) is currently estimated as the most prevalent chronic liver disease in all age groups. An increasing body of evidence obtained in experimental and clinical data indicates that oxidative stress is the most important pathogenic factor in the development of NAFLD. The study aimed to investigate the impact of α-lipoic acid (LA), widely used as an antioxidant, on the effects of a hypercaloric choline-deficient diet. Male Wistar rats were divided into three groups: control diet (C); hypercaloric choline-deficient diet (HCCD), and hypercaloric choline-deficient diet with α-lipoic acid (HCCD+LA). Supplementation of HCCD with LA for eight weeks led to a decrease in visceral adipose tissue/body weight ratio, the activity of liver glutathione peroxidase and paraoxonase-1, plasma, and liver total antioxidant activity, as well as an increase in liver/body weight ratio, liver total lipid and triglyceride content, and liver transaminase activities compared to the HCCD group without LA. In conclusion, our study shows that α-lipoic acid detains obesity development but exacerbates the severity of diet-induced oxidative stress and lipid accumulation in the liver of male Wistar rats fed a hypercaloric choline-deficient diet.     

Folic acid supplementation reduces oxidative stress and hepatic toxicity in rats treated chronically with ethanol

Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = 0.612^**), AST (r = 0.652^*), CD (r = 0.495^*), and TRAP (r = -0.486^*). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress.     

Effect of gallic acid on high fat diet-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats

Gallic acid (GA) is a naturally abundant plant phenolic compound in the human diet and is known to reduce the risk of disease. In this study, the anti-obesity effect of GA in an animal model of diet-induced obesity was investigated. Obesity was induced in male Wistar rats by feeding them a high-fat diet (HFD). GA was given as a supplement at the levels of 50 and 100 mg/kg rat for a period of 10 weeks. The results showed that the body weight, organ weight of the liver and adipose tissue weights of peritoneal and epididymal tissues in the HFD+GA groups were significantly decreased as compared with the HFD group. Serum TAG, phospholipid, total cholesterol, LDL-cholesterol, insulin and leptin levels in the HFD+GA groups were significantly decreased as compared with the HFD group. Histological study showed that the lipid droplets of rats with HFD+GA diets were significantly smaller than those with HFD diets. Hepatic TAG and cholesterol levels in HFD+GA groups were significantly decreased as compared with the HFD group. Moreover, the consumption of GA reduced oxidative stress and GSSG content and enhanced the levels of glutathione, GSH peroxidase, GSH reductase and GSH S-transferase in the hepatic tissue of rats with HFD-induced obesity. These results demonstrate that intake of GA can be beneficial for the suppression of HFD-induced dyslipidaemia, hepatosteatosis and oxidative stress in rats.     

Effects of a leucine and pyridoxine-containing nutraceutical on fat oxidation, and oxidative and inflammatory stress in overweight and obese subjects

Leucine stimulates tissue protein synthesis and may also attenuate adiposity by increasing fatty acid oxidation and mitochondrial biogenesis in muscle and adipocytes. Accordingly, the effects of a nutraceutical containing 2.25 g leucine and 30 mg pyridoxine (Vitamin B6) (NuFit active blend) were tested in cell culture and in a clinical trial. 3T3L1 adipocytes were treated with leucine (0.25 mM or 0.5 mM) and/or Pyridoxal Phosphate (PLP) (50 nM or 100 nM) for 48 h. For the clinical trial, twenty overweight or obese subjects received the NuFit active blend or placebo three times/day for 4 weeks without energy restriction. Leucine decreased fatty acid synthase (FAS) expression and triglyceride content in adipocytes, and PLP addition significantly augmented this effect. Administration of NuFit active blend in the clinical trial increased fat oxidation by 33.6 g/day (p < 0.04), decreased respiratory quotient, improved HOMA(IR), reduced oxidative and inflammatory biomarkers (plasma MDA, 8-isoprostane-F(2α), TNF-α, C-reactive protein), and increased the anti-inflammatory marker adiponectin. These data indicate that the NuFit active blend significantly increased fat oxidation and insulin sensitivity, and reduced oxidative and inflammatory stress. Therefore, the NuFit active blend appears to be a useful nutraceutical in the management of obesity and associated co-morbidities.     

Long-term vegetarians have low oxidative stress, body fat, and cholesterol levels

Excessive oxidative stress and abnormal blood lipids may cause chronic diseases. This risk can be reduced by consuming an antioxidant- and fiber-rich vegetarian diet. We compared biomarkers of oxidative stress, antioxidant capacity, and lipid profiles of sex- and age-matched long-term vegetarians and omnivores in Korea. Forty-five vegetarians (23 men and 22 women; mean age, 49.5 ± 5.3 years), who had maintained a vegetarian diet for a minimum of 15 years, and 30 omnivores (15 men and 15 women; mean age, 48.9 ± 3.6 years) participated in this study. Their 1-day, 24-h recall, and 2-day dietary records were analyzed. Oxidative stress was measured by the levels of diacron reactive oxygen metabolites (d-ROM). Antioxidant status was determined by the biological antioxidant potential (BAP) and levels of endogenous antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. We observed that vegetarians had a significantly lower body fat percentage (21.6 ± 6.4%) than that of omnivores (25.4 ± 4.6%; P < 0.004). d-ROM levels were significantly lower in vegetarians than those in omnivores (331.82 ± 77.96 and 375.80 ± 67.26 Carratelli units; P < 0.011). Additionally, total cholesterol levels in the vegetarians and omnivores were 173.73 ± 31.42 mg/dL and 193.17 ± 37.89 mg/dL, respectively (P < 0.018). Low-density lipoprotein cholesterol was 101.36 ± 23.57 mg/dL and 120.60 ± 34.62 mg/dL (P < 0.005) in the vegetarians and omnivores, respectively, indicating that vegetarians had significantly lower lipid levels. Thus, oxidative stress, body fat, and cholesterol levels were lower in long-term vegetarians than those in omnivores.     

Salvia plebeia R. Br. Water Extract Ameliorates Hepatic Steatosis in a Non-Alcoholic Fatty Liver Disease Model by Regulating the AMPK Pathway

Salvia plebeia R. Br. (SP), grown from autumn to spring, is used as a medicinal herb from roots to leaves. This herb exhibits antioxidant activities and various physiological effect, including anti-asthma, immune-promoting, anti-obesity, and anti-cholesterol effects. However, the effectiveness of SP against non-alcoholic fatty liver disease (NAFLD) and the associated mechanism have not been elucidated. In this study, alleviation of NAFLD by SP was confirmed in a mouse model of hepatic steatosis induced by a high-fat diet and in HepG2 cells administered free fatty acids (FFA). In the experimental model, intrahepatic lipid accumulation was investigated using the AdipoRed^TM assay, Oil Red O staining, biomarker analysis, and hematoxylin and eosin staining. Furthermore, glucose tolerance was examined based on the fasting glucose levels and oral glucose tolerance. The molecular mechanisms related to hepatic steatosis were determined based on marker mRNA levels. Blood FFAs were found to flow into the liver via the action of fatty acid translocase, cluster of differentiation 36, and fatty acid transporter proteins 2 and 5. Salvia plebeia R. Br. water extract (SPW) suppressed the FFAs inflow by regulating the expression of the above-mentioned proteins. Notably, modulating the expression of AMP-activated protein kinase (AMPK) and liver X receptor, which are involved in the regulation of lipid metabolism, stimulated peroxisome proliferator activated receptor α in the nucleus to induce the expression genes involved in β-oxidation and increase β-oxidation in the mitochondria. AMPK modulation also increased the expression of sterol regulatory element binding protein-1c, which activated lipid synthesis enzymes. As a consequence of these events, triglyceride synthesis was reduced and lipid accumulation in hepatocytes was alleviated. Overall, our findings suggested that SPW could ameliorate NAFLD by inhibiting hepatic steatosis through AMPK modulation.