The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE−/−FXR−/− Mice

Background: Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency.Methods: En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)−/− and ApoE−/−FXR−/− mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice.Results: Compared with ApoE−/− mice, ApoE−/−FXR−/− mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE−/−FXR−/− mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver).Conclusion: Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.

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Transgenerational impact of maternal obesogenic diet on offspring bile acid homeostasis and nonalcoholic fatty liver disease

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00474.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. E674-E686 ◽

Cited By ~ 3

Author(s):

Michael D. Thompson ◽

Alaina Derse ◽

Jeremie LA Ferey ◽

Michaela Reid ◽

Yan Xie ◽

...

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Maternal Obesity ◽

Maternal Diet ◽

Nonalcoholic Fatty Liver ◽

Periportal Fibrosis

Studies show maternal obesity is a risk factor for metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in offspring. Here we evaluated potential mechanisms underlying these phenotypes. Female C57Bl6 mice were fed chow or an obesogenic high-fat/high-sucrose (HF/HS) diet with subsequent mating of F1 and F2 female offspring to lean males to develop F2 and F3 generations, respectively. Offspring were fed chow or fibrogenic (high transfat, cholesterol, fructose) diets, and histopathological, metabolic changes, and bile acid (BA) homeostasis was evaluated. Chow-fed F1 offspring from maternal HF/HS lineages (HF/HS) developed periportal fibrosis and inflammation with aging, without differences in hepatic steatosis but increased BA pool size and shifts in BA composition. F1, but not F2 or F3, offspring from HF/HS showed increased steatosis on a fibrogenic diet, yet inflammation and fibrosis were paradoxically decreased in F1 offspring, a trend continued in F2 and F3 offspring. HF/HS feeding leads to increased periportal fibrosis and inflammation in chow-fed offspring without increased hepatic steatosis. By contrast, fibrogenic diet-fed F1 offspring from HF/HS dams exhibited worse hepatic steatosis but decreased inflammation and fibrosis. These findings highlight complex adaptations in NAFLD phenotypes with maternal diet.

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Resveratrol protects against nonalcoholic fatty liver disease by improving lipid metabolism and redox homeostasis via the PPARα pathway

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2019-0057 ◽

2020 ◽

Vol 45 (3) ◽

pp. 227-239 ◽

Cited By ~ 2

Author(s):

Yujie Huang ◽

Hedong Lang ◽

Ka Chen ◽

Yong Zhang ◽

Yanxiang Gao ◽

...

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Protein Kinase ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Hepg2 Cells ◽

Fatty Liver Disease ◽

Redox Homeostasis ◽

Nonalcoholic Fatty Liver

Resveratrol (RSV), a well-known bioactive compound, has been reported to exert a broad range of health benefits. Accumulating evidence suggests that RSV is beneficial for many metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). This study investigated the preventive and therapeutic effects of RSV on high-fat diet (HFD)-induced NAFLD in rats and palmitate acid (PA)-induced hepatocyte steatosis in HepG2 cells. Hepatocytes were incubated with inhibitors of peroxisome proliferator-activated receptor α (PPARα) or short interfering RNAs (siRNAs) targeting PPARα, AMP-activated protein kinase (AMPK), and protein kinase A (PKA) to determine the underlying mechanisms. We found that RSV noticeably ameliorated HFD-induced hepatic steatosis in rats and inhibited PA-induced lipid accumulation in HepG2 cells. Moreover, RSV improved lipid metabolism, enhanced antioxidant capacity, and restored mitochondrial respiratory chain activities. Incubation with inhibitors of PPARα or PPARα siRNA abolished the protective effects of RSV on lipid metabolism and redox homeostasis. Furthermore, RSV activated the PKA/AMPK/PPARα signaling pathway. Our results provided direct evidence for a novel, PPARα-mediated mechanism responsible for the beneficial effects of RSV on hepatic steatosis. These findings may have important theoretical and application prospects for the prevention and treatment of NAFLD. Novelty RSV improved lipid metabolism and redox homeostasis and oxidative stress in NAFLD via the PKA/AMPK/PPARα signaling pathway. RSV may have a greater beneficial effect in the early prevention of hepatic steatosis.

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Human Umbilical Cord-Derived Mesenchymal Stem Cell Therapy Ameliorates Nonalcoholic Fatty Liver Disease in Obese Type 2 Diabetic Mice

Stem Cells International ◽

10.1155/2019/8628027 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Bing Li ◽

Yu Cheng ◽

Songyan Yu ◽

Li Zang ◽

Yaqi Yin ◽

...

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Umbilical Cord ◽

Fatty Liver Disease ◽

Human Umbilical Cord ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is increasingly common among patients with type 2 diabetes mellitus (T2DM). The two conditions can act synergistically to produce adverse outcomes. However, the therapeutic options for patients with NAFLD and T2DM are currently limited. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) have shown therapeutic potential for diabetes and hepatic disorders such as liver cirrhosis and fulminant hepatic failure. The present study is aimed at investigating the effect of human UC-MSCs on a mouse model of NAFLD and T2DM, characterized by obesity-induced hyperglycaemia, dyslipidaemia, hepatic steatosis, and liver dysfunction. Thirty-week-old male C57BL/6 db/db mice were infused with human UC-MSCs or phosphate-buffered saline (PBS) via the tail vein once a week for six weeks. Age-matched male C57BL/6 wild-type db/+ mice were used as controls. Body weight and random blood glucose were measured every week. One week after the sixth infusion, intraperitoneal glucose tolerance tests and insulin tolerance tests were performed and the blood and liver were harvested for biochemical and histopathological examinations. Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), immunofluorescence staining, and western blot were performed to monitor the expression of the lipid metabolism- and regulatory pathway-related genes. UC-MSC infusions significantly ameliorated hyperglycaemia, attenuated the elevation of hepatic transaminases, and decreased lipid contents, including triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Moreover, histological lesions in the liver diminished markedly, as evidenced by reduced lipid accumulation and attenuated hepatic steatosis. Mechanistically, UC-MSCs were found to regulate lipid metabolism by increasing the expression of fatty acid oxidation-related genes and inhibiting the expression of lipogenesis-related genes, which were associated with the upregulation of the HNF4α-CES2 pathway. Our results demonstrate that human UC-MSCs can ameliorate NAFLD and reverse metabolic syndrome in db/db mice. Thus, UC-MSCs may serve as a novel therapeutic agent for T2DM patients with NAFLD.

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Dynamics of hepatic steatosis resolution and changes in gut microbiome with weight loss in nonalcoholic fatty liver disease

Obesity Science & Practice ◽

10.1002/osp4.476 ◽

2021 ◽

Author(s):

Jaideep Behari ◽

Lisa Graham ◽

Renwei Wang ◽

Claudiu Schirda ◽

Amir A. Borhani ◽

...

Keyword(s):

Weight Loss ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Gut Microbiome ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver

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Serum Bile Acid, Vitamin E, and Serotonin Metabolites Are Associated With Future Liver‐Related Events in Nonalcoholic Fatty Liver Disease

Hepatology Communications ◽

10.1002/hep4.1665 ◽

2021 ◽

Author(s):

Kara Wegermann ◽

Catherine Howe ◽

Ricardo Henao ◽

Ying Wang ◽

Cynthia D. Guy ◽

...

Keyword(s):

Liver Disease ◽

Bile Acid ◽

Vitamin E ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Serum Bile Acid ◽

Nonalcoholic Fatty Liver

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SGL 121 Attenuates Nonalcoholic Fatty Liver Disease through Adjusting Lipid Metabolism Through AMPK Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms21124534 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4534

Author(s):

Da Eun Kim ◽

Bo Yoon Chang ◽

Byeong Min Jeon ◽

Jong In Baek ◽

Sun Chang Kim ◽

...

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Signaling Pathway ◽

Hepg2 Cells ◽

Fatty Liver Disease ◽

Fatty Acid Synthase ◽

Density Lipoprotein ◽

Nonalcoholic Fatty Liver

A ginsenoside F2-enhanced mixture (SGL 121) increases the content of ginsenoside F2 by biotransformation. In the present study, we investigated the effect of SGL 121 on nonalcoholic fatty liver disease (NAFLD) in vitro and in vivo. High-fat, high-carbohydrate-diet (HFHC)-fed mice were administered SGL 121 for 12 weeks to assess its effect on improving NAFLD. In HepG2 cells, SGL 121 acted as an antioxidant, a hepatoprotectant, and had an anti-lipogenic effect. In NAFLD mice, SGL 121 significantly improved body fat mass; levels of hepatic triglyceride (TG), hepatic malondialdehyde (MDA), serum total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL); and activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In HepG2 cells, induced by oxidative stress, SGL 121 increased cytoprotection, inhibited reactive oxygen species (ROS) production, and increased antioxidant enzyme activity. SGL 121 activated the Nrf2/HO-1 signaling pathway and improved lipid accumulation induced by free fatty acids (FFA). Sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS) expression was significantly reduced in NAFLD-induced liver and HepG2 cells treated with SGL 121. Moreover, SGL 121 activated adenosine monophosphate-activated protein kinase (AMPK), which plays an important role in the regulation of lipid metabolism. The effect of SGL 121 on the improvement of NAFLD seems to be related to its antioxidant effects and activation of AMPK. In conclusion, SGL 121 can be potentially used for the treatment of NAFLD.

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Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00291.2013 ◽

2014 ◽

Vol 306 (6) ◽

pp. G496-G504 ◽

Cited By ~ 18

Author(s):

Akihiro Asai ◽

Pauline M. Chou ◽

Heng-Fu Bu ◽

Xiao Wang ◽

M. Sambasiva Rao ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Diet Group ◽

High Fat ◽

Nonalcoholic Fatty Liver ◽

Akt Phosphorylation ◽

High Carbohydrate

Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 wk old) were fed a high-fat and high-carbohydrate (HFHC) or control diet for 16 wk followed by the application of a combination of classic physiological, biochemical, and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level, homeostasis model assessment of IR, glucose intolerance, insulin intolerance, and AKT phosphorylation in adipose tissues, whereas the level of hepatic IR was determined by measuring insulin-triggered hepatic AKT phosphorylation. We discovered that both C57BL/6J and DBA/2J mice developed obesity to a similar degree without the feature of liver inflammation after being fed an HFHC diet for 16 wk. C57BL/6J mice in the HFHC diet group exhibited severe pan-lobular steatosis, a marked increase in hepatic triglyceride levels, and profound peripheral IR. In contrast, DBA/2J mice in the HFHC diet group developed only a mild degree of pericentrilobular hepatic steatosis that was associated with moderate changes in peripheral IR. Interestingly, both C57BL/6J and DBA/2J developed severe hepatic IR after HFHC diet treatment. Collectively, these data suggest that the severity of diet-induced hepatic steatosis is correlated to the level of peripheral IR, not with the severity of obesity and hepatic IR. Peripheral rather than hepatic IR is a dominant factor of pathophysiology in nonalcoholic fatty liver disease.

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Focal fatty sparing as an indicator of higher-grade fatty liver assessed by attenuation imaging: a prospective clinical study in NAFLD population

Zeitschrift für Gastroenterologie ◽

10.1055/a-1695-3637 ◽

2021 ◽

Author(s):

Elisabeth Miller ◽

Julian Schmidberger ◽

Wolfgang Kratzer

Keyword(s):

Liver Disease ◽

Clinical Study ◽

Fatty Liver ◽

Hepatic Steatosis ◽

Patient Population ◽

Fatty Liver Disease ◽

Fatty Degeneration ◽

Prospective Clinical Study ◽

Nonalcoholic Fatty Liver ◽

Attenuation Imaging

Abstract Background As part of a prospective clinical study, the degree of hepatic fatty degeneration was quantified in a patient population with nonalcoholic fatty liver disease and sonographically diagnosed with hepatic steatosis using attenuation imaging. Methods A total of 113 patients with hepatic steatosis were examined, of whom 35 showed focal fatty sparing. Patients with the condition after right nephrectomy, other known liver diseases, and relevant alcohol consumption were excluded from the evaluation. B-scan sonography and sonographic quantification of steatosis content using attenuation imaging (Aplio i800 Canon Medical Systems) were performed. Attenuation imaging is a new ultrasound-based measurement technique that allows objective detection and quantification of hepatic steatosis. Results The prevalence of focal fatty sparing was 31.0% in the patient population examined. Patients with focal fatty sparing showed a statistically significantly higher attenuation coefficient in contrast to patients without focal fatty sparing (0.79 ± 0.10 vs. 0.66 ± 0.09 dB/cm/MHz, p < 0.0001). Conclusion Detection of focal fatty sparing is associated with an increased attenuation coefficient and is thus an expression of higher-grade hepatic fatty degeneration. Patients with focal fatty sparing are more often male and have a higher BMI and a larger liver than patients with nonalcoholic fatty liver disease without focal fatty sparing.

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