Clinical Impact of Hepatic Steatosis in Patients with Chronic Hepatitis B Infection on Tenofovir Therapy

( Jeong Eun Song ),( Hye Won Lee ),( Beom Kyung Kim ),( Seung Up Kim ),( Do Young Kim ),( Sang Hoon Ahn ),( Kwang-hyub Han ),( Jun Yong Park ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1

Aims: The impact of superimposed non-alcoholic fatty liver disease (NAFLD) is well known in patients with chronic hepatitis C, however the impact in patients with chronic hepatitis B (CHB) is less distinct. We aimed to investigate the impact of NAFLD on virologic response to tenofovir treatment with chronic hepatitis B patients. Methods: This study was designed as a retrospective cohort study. Consecutive antiviral-naive CHB patients who visited our hospital between December 2012 and December 2013 and started tenofovir were identified from electronic medical record system. Based on controlled attenuated parameter (CAP), patients were divided into groups with hepatic steatosis (CAP score ≥ 260) and without hepatic steatosis (CAP score < 260). The impact of hepatic steatosis on the virologic response to tenofovir at 46 weeks of therapy was evaluated. We also investigated cumulative probabilities of achieving virologic response (VR) in CHB with and without hepatic steatosis using Kaplan-Meier analysis. Results: A total of 95 patients were involved in the study. Twenty eight out of 95 (28.3%) of CHB patinets had hepatic steatosis. The baseline characteristics, including age, sex, AST/ALT level, HBV DNA level and liver cirrhosis are not significantly different in both groups. However, CHB patients with hepatic steatosis had a higher body mass index (p < 0.05). The median duration of follow-up was 130 weeks (48-160 weeks). The VR rates in CHB patients at 46 weeks were 74.2% and 74.1% in CHB patients with and without hepatic steatosis, respectively (p>0.05). The cumulative probabilities of achieving VR were not significantly different in both groups (p>0.05). Conclusions: The presence of hepatic steatosis had no impact on the virologic response to tenofovir treatment.

Hepatic Fibrosis and Steatosis in Metabolic Syndrome

Venu Gopala Reddy Gangireddy,Courtney Pilkerton,Jun Xiang,Ruben Tinajero,Amie M. Ashcraft 대한비만학회 2022 The Korean journal of obesity Vol.31 No.1

Background: Metabolic syndrome (MetS) is a group of factors associated with increased risks of cardiovascular disease and overall mortality. Nonalcoholic fatty liver disease (NAFLD) is a common disorder that has been shown to cause hepatic steatosis and fibrosis. The relationship between NAFLD and MetS appears to be bidirectional, but very few studies have examined the role of MetS in hepatic steatosis and fibrosis. The present study investigated the relationships between MetS and its components and the severity of hepatic fibrosis and steatosis, and fibrosis independent of steatosis. Methods: The study was a cross-sectional population-based survey of 4,678 National Health and Nutrition Examination Survey participants from 2017 to 2018 in the United States. Hepatic fibrosis and steatosis were measured using liver elastography. The MetS components were assessed using demographic, examination, laboratory, and self-reported data. Results: Using survey-weighted population estimates, 26% of the population had steatosis, 7.5% had fibrosis, and 3.3% had fibrosis without steatosis. The adjusted odds ratio for any level of steatosis was 4.12 times higher (95% confidence interval [CI], 3.16–5.37) and any level of fibrosis was 3.34 times higher (95% CI, 2.26–4.94) among participants with MetS than those without. The adjusted odds ratio for fibrosis without steatosis is 2.67 times higher (95% CI, 1.47–4.87) among participants with MetS than those without. Conclusion: The presence of MetS significantly increases the risk of hepatic fibrosis and steatosis, providing evidence for MetS to be considered an additional independent risk factor for hepatic fibrosis together with other known etiologies.

Hepatic Steatosis Index in the Detection of Fatty Liver in Patients with Chronic Hepatitis B Receiving Antiviral Therapy

( Jin Won Chang ),( Hye Won Lee ),( Beom Kyung Kim ),( Jun Yong Park ),( Do Young Kim ),( Sang Hoon Ahn ),( Kwang-hyub Han ),( Seung Up Kim ) 대한소화기학회 2021 Gut and Liver Vol.15 No.1

Background/Aims: The hepatic steatosis index (HSI) is a noninvasive method to assess the severity of hepatic steatosis. Antiviral therapy (AVT) can impact aspartate aminotransferase and alanine aminotransferase levels, which are the main components of the HSI. Thus, we investigated the accuracy of the HSI in detecting hepatic steatosis in patients with chronic hepatitis B (CHB) receiving AVT, compared with those not receiving AVT and in those with nonalcoholic fatty liver disease (NAFLD). Methods: Patients with CHB or NAFLD who underwent a magnetic resonance imaging proton density fat fraction (MRI-PDFF) evaluation between March 2010 and March 2019 were recruited. Hepatic steatosis was diagnosed when the PDFF exceeded 5%. Area under the receiver operating characteristic curve (AUROC) analysis was used to assess the diagnostic accuracy of the HSI in the detection of hepatic steatosis. Results: The mean age of the study population (189 men and 116 women; 244 with CHB [184 with and 60 without AVT] and 61 with NAFLD) was 55.6 years. The AUROC values for detecting hepatic steatosis were similar between patients with CHB (0.727; p<0.001) and those with NAFLD (0.739; p=0.002). However, when patients with CHB were subdivided into those receiving and not receiving AVT, the AUROC value decreased slightly in patients with CHB receiving AVT compared to those without not receiving AVT (0.707; p=0.001 vs 0.779; p=0.001). Conclusions: Despite a slight attenuation, the diagnostic accuracy of the HSI in patients with CHB receiving AVT in detecting hepatic steatosis was still acceptable. Further large-scale studies are required for validation. (Gut Liver 2021;15:117-127)

Quantitative Evaluation of Hepatic Steatosis Using Normalized Local Variance in a Rat Model: Comparison with Histopathology as the Reference Standard

배재석,Jae Young Lee,Dong Ho Lee,Haeryoung Kim,Youngeun Lee,Joon Koo Han 대한영상의학회 2019 Korean Journal of Radiology Vol.20 No.9

ObjectiveTo evaluate the diagnostic performance of the normalized local variance (NLV) ultrasound technique in the assessment of hepatic steatosis, and to identify the factors that influence the NLV value using histopathological examination as the reference standard. Materials and MethodsForty male Sprague-Dawley rats were fed a methionine-choline-deficient diet for variable periods (0, 2, 4, 6, 8, 10, or 12 days or 2, 3, or 4 weeks; four rats per group). At the end of each diet duration, magnetic resonance spectroscopy (MRS) and NLV examination were performed. Thereafter, the rats were sacrificed and their livers were histopathologically evaluated. Receiver operating characteristic (ROC) curve analysis was performed to assess the diagnostic capability of the NLV value in the detection of varying degrees of hepatic steatosis. Univariate and multivariate linear regressions were used to determine the factors associated with the NLV value. ResultsThe areas under the ROC curve for the detection of mild, moderate, and severe hepatic steatosis were 0.953, 0.896, and 0.735, respectively. The NLV value showed comparable diagnostic performance to that of MRS in the detection of ≥ mild or ≥ moderate hepatic steatosis. Multivariate linear regression analysis revealed that the degree of hepatic steatosis was the only significant factor affecting the NLV value (p < 0.001). ConclusionThe NLV value of ultrasound demonstrated satisfactory diagnostic performance in the assessment of varying degrees of hepatic steatosis. The degree of hepatic steatosis was the only significant factor that affected the NLV value.

Barley sprout extracts reduce hepatic lipid accumulation in ethanol-fed mice by activating hepatic AMP-activated protein kinase

Kim, Y.J.,Hwang, S.H.,Jia, Y.,Seo, W.D.,Lee, S.J. Published on behalf of the Canadian Institute of F 2017 Food Research International Vol.101 No.-

<P>Chronic alcohol consumption leads to hepatic lipid accumulation and alcoholic fatty liver disease. Previously, we demonstrated that barley sprout extract, which contains saponarin as an active compound, reduces hepatic steatosis. In this study, we investigated the effect of barley sprout extracts (BSE) on hepatic lipid accumulation in a mouse model of alcoholic fatty liver disease. Seven-week-old C57BL/6 mice were fed an alcohol-containing diet (5% ethanol) and a low or high dose of BSE (100 or 200 mg/kg body weight, respectively) for 10 days. The high dose of BSE significantly decreased hepatic lipid accumulation compared with the ethanol-only control group. In the second animal study, mice were fed an alcohol-containing diet for 10 days, followed by a 45% high fat diet with oral administration of BSE (100 or 200 mg/day/kg body weight) for 4 weeks. Mice in both BSE-fed groups showed reduced hepatic steatosis. In the livers of mice fed BSE, phosphorylation of AMP-activated protein kinase (AMPK) was increased, and expression of hepatic autophagy markers was elevated. In cultured hepatocytes, BSE (200 (mu g/mL) increased the rate of fatty acid oxidation and reduced that of fatty acid synthesis. Taken together, these findings suggest that BSE promotes degradation of lipid droplets and subsequent activation of fat oxidation by activating AMPK in the liver, thus protecting against development of hepatic steatosis in alcohol-fed mice. Saponarin, a major flavonoid in BSE and an activator of AMPK, increased the activity of microsomal triglyceride transfer protein, which suggests that the reduction in hepatic triglyceride levels was mediated by this component of BSE. In conclusion, BSE ameliorated hepatic steatosis in a mouse model of ethanol-induced fatty liver by activating AMPK, an effect possibly mediated by the saponarin component.</P>

Ginseng berry extract enhances metformin efficacy against obesity and hepatic steatosis in mice fed high-fat diet through increase of metformin uptake in liver

Chae, Hee-Sung,You, Byoung Hon,Choi, Junjeong,Chin, Young-Won,Kim, Hojun,Choi, Han Seok,Choi, Young Hee ELSEVIER SCIENCE B.V.; AMSTERDAM 2019 JOURNAL OF FUNCTIONAL FOODS Vol.62 No.-

<P><B>Abstract</B></P> <P>Ginseng berry extract contains plenty of ginsenosides showing anti-obesity and anti-hyperglycemic activities. Regarding that long-term intakes of herbal products to control metabolic disorders as popular alternatives have become popular, ginseng berry extract plus metformin is an attractive item for long-term glycemic control. Herein, we investigated the effect of ginseng berry extract (GBE) or its combination with metformin against obesity and hepatic steatosis in high-fat diet fed mice.</P> <P>GBE altered abnormal features (e.g. body weight, serum profiles, hepatic steatosis/inflammation and fat mass). Concomitantly, GBE increased mRNA levels of adiponectin and CCAAT/enhancer binding protein. All these changes were observed in metformin alone and GBE plus metformin. Moreover, in GBE plus metformin intake, GBE increased organic cation transporter-mediated metformin uptake in liver and mRNA of AMP-activated protein kinase together, which additively ameliorated obesity and hepatic steatosis. Therefore, GBE itself and GBE plus metformin could be useful to regulate metabolic disorders.</P> <P><B>Highlights</B></P> <P> <UL> <LI> GBE ameliorated obesity and hepatic steatosis in mice fed high-fat diet. </LI> <LI> GBE increased organic cation transporter-mediated metformin uptake in liver. </LI> <LI> GBE plus metformin additively ameliorated obesity and hepatic steatosis. </LI> <LI> GBE itself and GBE plus metformin could be useful to regulate metabolic disorders. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>In GBE plus metformin treatment, GBE plus metformin showed the additive efficacy against obesity, hepatic steatosis and hyperglycemia!</P> <P>[DISPLAY OMISSION]</P>

Oleuropein attenuates hepatic steatosis induced by high-fat diet in mice

Park, Soyoung,Choi, Youngshim,Um, Soo-Jong,Yoon, Seung Kew,Park, Taesun Elsevier 2011 Journal of hepatology Vol.54 No.5

<P><B>Background & Aims</B></P><P>Oleuropein, a secoiridoid derived from olives and olive oil, has been known to possess antimicrobial, antioxidative, and anticancer activities. The purpose of the present study was to determine whether oleuropein has a protective effect against hepatic steatosis induced by a high fat diet (HFD) and to elucidate its underlying molecular mechanisms in mice.</P><P><B>Methods</B></P><P>Male C57BL/6N mice were fed a normal diet (ND), HFD, or an oleuropein-supplemented diet (OSD) for 10weeks. The plasma and hepatic lipid levels were determined, and the hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively.</P><P><B>Results</B></P><P>The supplementation of HFD with oleuropein reversed the HFD-induced increases in liver weight along with plasma and hepatic lipid levels in mice. The expression of Wnt10b inhibitor genes, such as secreted firizzed-related sequence protein 5 and dickkopf homolog 2, was downregulated, whereas the β-catenin protein expression was upregulated in the liver of OSD-fed mice compared to HFD-fed mice. Fibroblast growth factor receptor 1 (FGFR1), phosphoextracellular-signal-regulated kinase 1/2, cyclin D, and E2F transcription factor 1, along with several key transcription factors and their target genes involved in adipogenesis, were downregulated by oleuropein. OSD-fed mice exhibited decreased expression of the toll-like-receptor-(TLR)-mediated signaling molecules (TLR2, TLR4, and myeloid differentiation primary-response gene 88) and proinflammatory cytokines, in their livers, as compared to HFD mice.</P><P><B>Conclusions</B></P><P>These results suggest that the protective effects of oleuropein against HFD-induced hepatic steatosis in mice appear to be associated with the Wnt10b- and FGFR1-mediated signaling cascades involved in hepatic lipogenesis, along with the TLR2- and TLR4-mediated signaling implicated in hepatic steatosis.</P>

Kimchi methanol extracts attenuate hepatic steatosis induced by high cholesterol diet in low-density lipoprotein receptor knockout mice through inhibition of endoplasmic reticulum stress

Woo, Minji,Kim, Mijeong,Noh, Jeong Sook,Song, Yeong Ok Elsevier 2017 Journal of Functional Foods Vol.32 No.-

<P><B>Abstract</B></P> <P>This study was examined inhibitory effects of kimchi with antioxidant, lipid lowering, and antiinflammatory activities on hepatic steatosis by suppression of endoplasmic reticulum (ER) stress in high cholesterol diet (HCD)-fed low-density lipoprotein receptor knockout mice. Animals were fed HCD for 8weeks with oral administration of kimchi methanol extracts (200mg/kgbw/day) (kimchi group, n=10) or distilled water as a vehicle (control group, n=10). In kimchi group, hepatic lipid peroxidation was reduced. Protein expression of ER stress molecules such as GRP78, p-PERK, p-eIF2α, XBP1, and CHOP were decreased. In addition, protein expression of anti-apoptotic molecules were increased, but those for the pro-apoptotic molecules were decreased. Protein expression of antioxidant enzymes regulated by Nrf2 was elevated. Histological analysis showed that hepatic steatosis, inflammation, and apoptosis in the kimchi group were less severe. In conclusion, hepatic steatosis induced by HCD can be alleviated by kimchi via suppressing ER stress.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Kimchi, fermented food with health benefits reduced hepatic lipid peroxidation. </LI> <LI> Endoplasmic reticulum stress-related molecules decreased by kimchi intake. </LI> <LI> Antioxidant enzymes increased by kimchi intake. </LI> <LI> Kimchi inhibited pro-apoptotic molecules and elevated anti-apoptotic molecules. </LI> <LI> Histological analysis supported kimchi suppressed hepatic steatosis. </LI> </UL> </P>

New mechanisms contributing to hepatic steatosis: glucose, insulin, and lipid signaling

이유정,김원호,김재우,유정환 한국통합생물학회 2014 Animal cells and systems Vol.18 No.2

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease and can lead to hepaticcirrhosis with liver failure. NAFLD is common in individuals who have obesity, diabetes, dyslipidemia, and/orhypertension. NAFLD comprises a wide spectrum of liver lesions ranging from mild hepatic steatosis to nonalcoholicsteatohepatitis (NASH), the most aggressive form. Hepatic steatosis, also called fatty liver, is the hallmark of NAFLD and isdefined as excess intrahepatic triglyceride (TG) content (≥5% of liver volume or weight). In some cases, the fataccumulation is associated with steatohepatitis, inflammation, and fibrous change of the liver. Studies on the regulation ofde novo fatty acid synthesis have revealed the mechanism leading to hepatic steatosis, mostly emphasizing the roles oftranscriptional regulation of enzymes involved in lipid metabolic pathway. Recently, high-fat diet-induced hepatic lipidaccumulation has also been associated with hepatocyte uptake of fatty acids from lipolyzed TG in adipose tissue, as well ashepatic TG incorporation. This review discusses a conceptual framework of how hepatic TG accumulation contributes tohepatic steatosis.

Protective Effects of <i>Alisma orientale</i> Extract against Hepatic Steatosis via Inhibition of Endoplasmic Reticulum Stress

Jang, Min-Kyung,Han, Yu-Ran,Nam, Jeong Soo,Han, Chang Woo,Kim, Byung Joo,Jeong, Han-Sol,Ha, Ki-Tae,Jung, Myeong Ho MDPI 2015 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.16 No.11

<P>Endoplasmic reticulum (ER) stress is associated with the pathogenesis of hepatic steatosis. <I>Alisma orientale</I> Juzepzuk is a traditional medicinal herb for diuretics, diabetes, hepatitis, and inflammation. In this study, we investigated the protective effects of methanol extract of the tuber of <I>Alisma orientale</I> (MEAO) against ER stress-induced hepatic steatosis <I>in vitro</I> and <I>in vivo</I>. MEAO inhibited the tunicamycin-induced increase in luciferase activity of ER stress-reporter constructs containing ER stress response element and ATF6 response element. MEAO significantly inhibited tunicamycin-induced ER stress marker expression including GRP78, CHOP, and XBP-1 in tunicamycin-treated Human hepatocellular carcinoma (HepG2) cells and the livers of tunicamycin-injected mice. It also inhibited tunicamycin-induced accumulation of cellular triglyceride. Similar observations were made under physiological ER stress conditions such as in palmitate (PA)-treated HepG2 cells and the livers of high-fat diet (HFD)-induced obese mice. MEAO repressed hepatic lipogenic gene expression in PA-treated HepG2 cells and the livers of HFD obese mice. Furthermore, MEAO repressed very low-density lipoprotein receptor (VLDLR) expression and improved ApoB secretion in the livers of tunicamycin-injected mice or HFD obese mice as well as in tunicamycin or PA-treated HepG2 cells. Alismol, a guaiane-type sesquiterpenes in <I>Alisma orientale</I>, inhibited GRP78 expression in tunicamycin-treated HepG2 cells. In conclusion, MEAO attenuates ER stress and prevents hepatic steatosis pathogenesis via inhibition of expression of the hepatic lipogenic genes and VLDLR, and enhancement of ApoB secretion.</P>