scholarly journals Sexually Dimorphic Responses to a High-Refined Carbohydrate Diet in a Nonalcoholic Fatty Liver Disease Mouse Model

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 16-16
Author(s):  
Michael Daniels ◽  
Chun Liu ◽  
Kang-Quan Hu ◽  
Xiang-Dong Wang
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Sexually Dimorphic ◽  
Male Mice ◽  
Carbohydrate Diet ◽  
Nonalcoholic Fatty Liver ◽  
Female Mice

Abstract Objectives Nonalcoholic fatty liver disease (NAFLD) incidence and prevalence have been reported to be higher in men than women, however, the effects of sexual dimorphism on NAFLD risk and progression have not been adequately examined. Our lab has previously shown that a liquid high-refined carbohydrate diet (HRCD) induced more severe hepatic steatosis compared to an isocaloric high fat diet in male mice. Also, HRCD-induced reduction in sirtuin 1 (SIRT1), an NAD-dependent deacetylase protein, has previously been implicated in NAFLD pathogenesis. Therefore, we investigated whether there were sexually dimorphic responses to a liquid high-refined carbohydrate diet (HRCD) in male and female, wildtype and SIRT1-deficient mice. Methods Male and female 10–12-week-old wildtype (SIRT1 +/+: n = 12; M = 6, F = 6) and mice carrying a heterozygous H355Y SIRT1 point mutation (SIRT1 +/y: n = 14; M = 7, F = 7) were both fed a HRCD (Lieber-DeCarli liquid diet supplemented with maltose dextrin; 47% energy from refined carbohydrate, Dyets, #710,260) for 5 weeks and 9 weeks. Hepatic gene expression was examined using qRT-PCR. Plasma ALT (alanine transaminase) and hepatic MDA (malondialdehyde) levels were determined using colorimetric assay kits. Hepatic steatosis scoring was conducted by analyzing Hematoxylin and Eosin (H&E) stains. Results 9 weeks of HRCD induced significantly less hepatic steatosis in female mice irrespective of genotype compared to male mice as determined by grading of H&E stains (P < 0.05). Furthermore, liver expression of several fatty acid oxidation genes (CPT1, ACOX1) was significantly higher in females (P < 0.05), which potentially suggests increased fatty acid oxidation. Additionally, female mice had significantly increased antioxidant gene expression (GPX4, SOD1, SOD2, Catalase) and significantly lower hepatic MDA (P < 0.05), which indicate an increased capacity to mitigate oxidative stress. Lastly, plasma ALT levels were significantly lower in females compared to males after 9 weeks of HRCD (P < 0.05). Conclusions Collectively, these data indicate that female mice are moderately protected against HRCD-induced NAFLD compared to male mice, potentially through increased hepatic fatty acid oxidation and superior mitigation of oxidative stress due to increased antioxidant system gene expression in the liver. Funding Sources HNRCA, USDA/ARS Grants.

scholarly journals Aurantio-Obtusin Attenuates Non-Alcoholic Fatty Liver Disease Through AMPK-Mediated Autophagy and Fatty Acid Oxidation Pathways

2022 ◽  
Vol 12 ◽  
Author(s):  
Fei Zhou ◽  
Mingning Ding ◽  
Yiqing Gu ◽  
Guifang Fan ◽  
Chuanyang Liu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD), manifested as the aberrant accumulation of lipids in hepatocytes and inflammation, has become an important cause of advanced liver diseases and hepatic malignancies worldwide. However, no effective therapy has been approved yet. Aurantio-obtusin (AO) is a main bioactive compound isolated from Cassia semen that has been identified with multiple pharmacological activities, including improving adiposity and insulin resistance. However, the ameliorating effects of AO on diet-induced NAFLD and underlying mechanisms remained poorly elucidated. Our results demonstrated that AO significantly alleviated high-fat diet and glucose-fructose water (HFSW)-induced hepatic steatosis in mice and oleic acid and palmitic acid (OAPA)-induced lipid accumulation in hepatocytes. Remarkably, AO was found to distinctly promote autophagy flux and influence the degradation of lipid droplets by inducing AMPK phosphorylation. Additionally, the induction of AMPK triggered TFEB activation and promoted fatty acid oxidation (FAO) by activating PPARα and ACOX1 and decreasing the expression of genes involved in lipid biosynthesis. Meanwhile, the lipid-lowing effect of AO was significantly prevented by the pretreatment with inhibitors of autophagy, PPARα or ACOX1, respectively. Collectively, our study suggests that AO ameliorates hepatic steatosis via AMPK/autophagy- and AMPK/TFEB-mediated suppression of lipid accumulation, which opens new opportunities for pharmacological treatment of NAFLD and associated complications.

scholarly journals Gomisin N Alleviates Ethanol-Induced Liver Injury through Ameliorating Lipid Metabolism and Oxidative Stress

2018 ◽  
Vol 19 (9) ◽  
pp. 2601 ◽  
Author(s):  
Arulkumar Nagappan ◽  
Dae Jung ◽  
Ji-Hyun Kim ◽  
Hoyoung Lee ◽  
Myeong Jung
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Fatty Acid ◽  
Liver Injury ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Antioxidant Genes ◽  
Gomisin N

Gomisin N (GN), a lignan derived from Schisandra chinensis, has been shown to possess antioxidant, anti-inflammatory, and anticancer properties. In the present study, we investigated the protective effect of GN against ethanol-induced liver injury using in vivo and in vitro experiments. Histopathological examination revealed that GN administration to chronic-binge ethanol exposure mice significantly reduced ethanol-induced hepatic steatosis through reducing lipogenesis gene expression and increasing fatty acid oxidation gene expression, and prevented liver injury by lowering the serum levels of aspartate transaminase and alanine transaminase. Further, it significantly inhibited cytochrome P450 2E1 (CYP2E1) gene expression and enzyme activity, and enhanced antioxidant genes and glutathione level in hepatic tissues, which led to decreased hepatic malondialdehyde levels. It also lowered inflammation gene expression. Finally, GN administration promoted hepatic sirtuin1 (SIRT1)-AMP-activated protein kinase (AMPK) signaling in ethanol-fed mice. Consistent with in vivo data, treatment with GN decreased lipogenesis gene expression and increased fatty acid oxidation gene expression in ethanol-treated HepG2 cells, thereby preventing ethanol-induced triglyceride accumulation. Furthermore, it inhibited reactive oxygen species generation by downregulating CYP2E1 and upregulating antioxidant gene expression, and suppressed inflammatory gene expression. Moreover, GN prevented ethanol-mediated reduction in SIRT1 and phosphorylated AMPK. These findings indicate that GN has therapeutic potential against alcoholic liver disease through inhibiting hepatic steatosis, oxidative stress and inflammation.

scholarly journals Nordihydroguaiaretic acid improves metabolic dysregulation and aberrant hepatic lipid metabolism in mice by both PPARα-dependent and -independent pathways

2013 ◽  
Vol 304 (1) ◽  
pp. G72-G86 ◽  
Author(s):  
Haiyan Zhang ◽  
Wen-Jun Shen ◽  
Yuan Cortez ◽  
Fredric B. Kraemer ◽  
Salman Azhar
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Nordihydroguaiaretic Acid ◽  
Acid Oxidation ◽  
Hepatic Gene Expression ◽  
Creosote Bush ◽  
Fatty Acid Catabolism

Creosote bush-derived nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, possesses antioxidant properties and functions as a potent antihyperlipidemic agent in rodent models. Here, we examined the effect of chronic NDGA treatment of ob/ob mice on plasma dyslipidemia, hepatic steatosis, and changes in hepatic gene expression. Feeding ob/ ob mice a chow diet supplemented with either low (0.83 g/kg diet) or high-dose (2.5 g/kg diet) NDGA for 16 wk significantly improved plasma triglyceride (TG), inflammatory chemokine levels, hyperinsulinemia, insulin sensitivity, and glucose intolerance. NDGA treatment caused a marked reduction in liver weight and TG content, while enhancing rates of fatty acid oxidation. Microarray analysis of hepatic gene expression demonstrated that NDGA treatment altered genes for lipid metabolism, with genes involved in fatty acid catabolism most significantly increased. NDGA upregulated the mRNA and nuclear protein levels of peroxisome proliferator-activated receptor α (PPARα), and the activated (phosphorylated) form of AMP-activated kinase. NDGA increased PPARα promoter activity in AML12 hepatocytes and also prevented the fatty acid suppression of PPARα expression. In contrast, PPARα siRNA abrogated the stimulatory effect of NDGA on fatty acid catabolism. Likewise, no stimulatory effect of NDGA on hepatic fatty acid oxidation was observed in the livers of PPARα-deficient mice, but the ability of NDGA to reverse fatty liver conditions was unaffected. In conclusion, the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation via PPARα-dependent pathways. However, PPARα-independent pathways also contribute to NDGA's action to ameliorate hepatic steatosis.

scholarly journals PPARα-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation

2015 ◽  
Vol 185 (5) ◽  
pp. 1396-1408 ◽  
Author(s):  
Qian Gao ◽  
Yuzhi Jia ◽  
Gongshe Yang ◽  
Xiaohong Zhang ◽  
Prajwal C. Boddu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Obese Mice

scholarly journals Critical Role for Hepatocyte-Specific eNOS in NAFLD and NASH

2021 ◽  
Author(s):  
Rory P. Cunningham ◽  
Mary P. Moore ◽  
Ryan J. Daskek ◽  
Grace M. Meers ◽  
Takamune Takahashi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Critical Role ◽  
Acid Oxidation ◽  
Mitochondrial Fatty Acid Oxidation ◽  
Nonalcoholic Fatty Liver ◽  
Mitochondrial Fatty Acid ◽  
Endothelial Nitric Oxide

Regulation of endothelial nitric oxide synthase (eNOS) in hepatocytes may be an important target in nonalcoholic fatty liver disease (NAFLD) development and progression to steatohepatitis (NASH). In this study, we show genetic deletion and viral knockdown of hepatocyte-specific eNOS exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, increased mitochondrial H<sub>2</sub>O<sub>2</sub> emission, and impaired the hepatic mitophagic (BNIP3 and LC3II) response. Conversely, overexpressing eNOS in hepatocytes in vitro and in vivo increased hepatocyte mitochondrial respiration and attenuated western diet induced NASH. Moreover, patients with elevated NAFLD activity score (histology score of worsening steatosis, hepatocyte ballooning, and inflammation) exhibited reduced hepatic eNOS expression which correlated with reduced hepatic mitochondrial fatty acid oxidation and lower hepatic protein expression of mitophagy protein BNIP3. The current study reveals an important molecular role for hepatocyte-specific eNOS as a key regulator of NAFLD/NASH susceptibility and mitochondrial quality control with direct clinical correlation to patients with NASH.

scholarly journals Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-induced Weight Gain in Male Mice

2020 ◽  
Author(s):  
E. Matthew Morris ◽  
Roberto D. Noland ◽  
Michael E. Ponte ◽  
Michelle L. Montonye ◽  
Julie A. Christianson ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Weight Gain ◽  
Energy Metabolism ◽  
Energy Balance ◽  
Fatty Acid Oxidation ◽  
Positive Energy ◽  
Acid Oxidation ◽  
Male Mice ◽  
Short Term

AbstractCentral integration of peripheral neural signals is one mechanism by which systemic energy homeostasis is regulated. Previous work described increased acute food intake following chemical reduction of hepatic fatty acid oxidation and ATP levels, which was prevented by common hepatic branch vagotomy (HBV). However, possible offsite actions of the chemical compounds confound the precise role of liver energy metabolism. Herein, we used a liver-specific PGC1a heterozygous (LPGC1a) mouse model, with associated reductions in mitochondrial fatty acid oxidation and respiratory capacity, to assess the role of liver energy metabolism in systemic energy homeostasis. LPGC1a male mice have 70% greater high-fat/high-sucrose (HFHS) diet-induced weight gain and 35% greater positive energy balance compared to wildtype (WT) (p<0.05). The greater energy balance was associated with altered feeding behavior and lower activity energy expenditure during HFHS in LPGC1a males. Importantly, no differences in HFHS-induced weight gain or energy metabolism was observed between female WT and LPGC1a mice. WT and LPGC1a mice underwent sham or HBV to assess whether vagal signaling was involved in HFHS-induced weight gain of male LPGC1a mice. HBV increased HFHS-induced weight gain (85%, p<0.05) in male WT, but not LPGC1a mice. As above, sham LPGC1a males gain 70% more weight during short-term HFHS feeding than sham WT (p<0.05). These data demonstrate a sexspecific role of reduced liver energy metabolism in acute diet-induced weight gain, and the need of more nuanced assessment of the role of vagal signaling in short-term diet-induced weight gain.Key Points SummaryReduced liver PGC1a expression results in reduced mitochondrial fatty acid oxidation and respiratory capacity in male mice.Male mice with reduced liver PGC1a expression (LPGC1a) demonstrate greater short-term high-fat/high-sucrose diet-induced weight gain compared to wildtype.Greater positive energy balance during HFHS feeding in male LPGC1a mice is associated with altered food intake patterns and reduced activity energy expenditure.Female LPGC1a mice do not have differences in short-term HFHS-induced body weight gain or energy metabolism compared to wildtype.Disruption of vagal signaling through common hepatic branch vagotomy increases short-term HFHS-induced weight gain in male wildtype mice, but does not alter male LPGC1a weight gain.

scholarly journals Tang-Nai-Kang Alleviates Pre-diabetes and Metabolic Disorders and Induces a Gene Expression Switch toward Fatty Acid Oxidation in SHR.Cg-Leprcp/NDmcr Rats

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0122024 ◽  
Author(s):  
Linyi Li ◽  
Hisae Yoshitomi ◽  
Ying Wei ◽  
Lingling Qin ◽  
Jingxin Zhou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Disorders ◽  
Acid Oxidation

scholarly journals Correction: Black bean protein concentrate ameliorates hepatic steatosis by decreasing lipogenesis and increasing fatty acid oxidation in rats fed a high fat-sucrose diet

2021 ◽  
Author(s):  
Irma Hernandez-Velazquez ◽  
Monica Sanchez-Tapia ◽  
Guillermo Ordaz-Nava ◽  
Nimbe Torres ◽  
Armando R. Tovar ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Protein Concentrate ◽  
High Fat ◽  
Black Bean ◽  
Sucrose Diet ◽  
Bean Protein

Correction for ‘Black bean protein concentrate ameliorates hepatic steatosis by decreasing lipogenesis and increasing fatty acid oxidation in rats fed a high fat-sucrose diet’ by Irma Hernandez-Velazquez et al., Food Funct., 2020, DOI: 10.1039/d0fo02258f.

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