Pycnogenol protects against diet-induced hepatic steatosis in apolipoprotein-E-deficient mice

PycnogenolR (PYC), a combination of active flavonoids derived from French maritime pine bark, is a natural antioxidant that has various pharmacological activities. Here, we investigated the beneficial effect of PYC on diet-induced hepatic steatosis. Apolipoprotein E (ApoE)-deficient male mice were administered PYC at oral doses of 30 or 100 mg·kg−1·day−1 for 2 wk in advance and were then fed a high-cholesterol and -fat diet (HCD) for 8 wk. Biochemical, immunohistochemical, and gene expression analyses were conducted to explore the effect of PYC on lipid metabolism in ApoE-deficient mice on a HCD. Short-term treatment with HCD in ApoE-deficient mice induced hepatic injuries, such as lipid metabolism disorder and hepatic histopathological changes. We found that PYC reduced body weight and the increase of serum lipids that had been caused by HCD. Supplementation of PYC significantly reduced lipid deposition in the liver, as shown by the lowered hepatic lipid content and histopathological lesions. We subsequently detected genes related to lipid metabolism and inflammatory cytokines. The study showed that PYC markedly suppressed the expression of genes related to hepatic lipogenesis, fatty acid uptake, and lipid storage while increasing the lipolytic gene, which thus reduced hepatic lipid content. Furthermore, PYC mainly reduced the expression of inflammatory cytokines and the infiltration of inflammatory cells, which were resistant to the development of hepatic steatosis. These results demonstrate that PYC protects against the occurrence and development of hepatic steatosis and may provide a new prophylactic approach for nonalcoholic fatty liver disease (NAFLD).

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Template to improve glycemic control without reducing adiposity or dietary fat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00703.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. E779-E789 ◽

Cited By ~ 49

Author(s):

R. Krishnapuram ◽

E. J. Dhurandhar ◽

O. Dubuisson ◽

H. Kirk-Ballard ◽

S. Bajpeyi ◽

...

Keyword(s):

Glycemic Control ◽

Cell Signaling ◽

Glucose Uptake ◽

Hepatic Steatosis ◽

Lipid Content ◽

Insulin Signaling ◽

Dietary Fat ◽

Hepatic Lipid ◽

Chronic Hyperglycemia ◽

Hepatic Lipid Content

Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.

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Inhibition of Ghrelin Activity by Receptor Antagonist [d-Lys-3] GHRP-6 Attenuates Alcohol-Induced Hepatic Steatosis by Regulating Hepatic Lipid Metabolism

Biomolecules ◽

10.3390/biom9100517 ◽

2019 ◽

Vol 9 (10) ◽

pp. 517 ◽

Cited By ~ 2

Author(s):

Karuna Rasineni ◽

Jacy L. Kubik ◽

Carol A. Casey ◽

Kusum K. Kharbanda

Keyword(s):

Insulin Secretion ◽

Fatty Acid ◽

Lipid Metabolism ◽

Receptor Antagonist ◽

Hepatic Steatosis ◽

De Novo ◽

Serum Insulin ◽

Acid Uptake ◽

Hepatic Lipid ◽

Insulin Levels

Alcoholic steatosis, characterized by an accumulation of triglycerides in hepatocytes, is one of the earliest pathological changes in the progression of alcoholic liver disease. In our previous study, we showed that alcohol-induced increase in serum ghrelin levels impair insulin secretion from pancreatic β-cells. The consequent reduction in the circulating insulin levels promote adipose-derived fatty acid mobilization to ultimately contribute to hepatic steatosis. In this study, we determined whether inhibition of ghrelin activity in chronic alcohol-fed rats could improve hepatic lipid homeostasis at the pancreas–adipose–liver axis. Adult Wistar rats were fed Lieber-DeCarli control or an ethanol liquid diet for 7 weeks. At 6 weeks, a subset of rats in each group were injected with either saline or ghrelin receptor antagonist, [d-Lys-3] GHRP-6 (DLys; 9 mg/kg body weight) for 5 days and all rats were sacrificed 2 days later. DLys treatment of ethanol rats improved pancreatic insulin secretion, normalized serum insulin levels, and the adipose lipid metabolism, as evidenced by the decreased serum free fatty acids (FFA). DLys treatment of ethanol rats also significantly decreased the circulating FFA uptake, de novo hepatic fatty acid synthesis ultimately attenuating alcoholic steatosis. To summarize, inhibition of ghrelin activity reduced alcoholic steatosis by improving insulin secretion, normalizing serum insulin levels, inhibiting adipose lipolysis, and preventing fatty acid uptake and synthesis in the liver. Our studies provided new insights on the important role of ghrelin in modulating the pancreas–adipose–liver, and promoting adipocyte lipolysis and hepatic steatosis. The findings offer a therapeutic approach of not only preventing alcoholic liver injury but also treating it.

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Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00396.2016 ◽

2017 ◽

Vol 312 (4) ◽

pp. E244-E252 ◽

Cited By ~ 30

Author(s):

Terry D. Hinds ◽

Peter A. Hosick ◽

Shujuan Chen ◽

Robert H. Tukey ◽

Michael W. Hankins ◽

...

Keyword(s):

Hepatic Steatosis ◽

Lipid Content ◽

Transcriptional Activity ◽

Fasting Blood Glucose ◽

Humanized Mice ◽

Gilbert’S Syndrome ◽

Hepatic Lipid ◽

Insulin Levels ◽

Gilbert's Syndrome ◽

Hepatic Lipid Content

Gilbert’s syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic UGT1A1 gene that results in decreased conjugation and increased levels of unconjugated bilirubin. Recently, we have shown that bilirubin binds directly to the fat-burning nuclear peroxisome proliferator-activated receptor-α (PPARα). Additionally, we have shown that serine 73 phosphorylation [Ser(P)73] of PPARα decreases activity by reducing its protein levels and transcriptional activity. The aim of this study was to determine whether humanized mice with the Gilbert’s polymorphism (HuUGT*28) have increased PPARα activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert’s mutation (HuUGT*28) have reduced hepatic lipids, we placed them and C57BL/6J control mice on a high-fat (60%) diet for 36 wk. Body weights, fat and lean mass, and fasting blood glucose and insulin levels were measured every 6 wk throughout the investigation. At the end of the study, hepatic lipid content was measured and PPARα regulated genes as well as immunostaining of Ser(P)73 PPARα from liver sections. The HuUGT*28 mice had increased serum bilirubin, lean body mass, decreased fat mass, and hepatic lipid content as well as lower serum glucose and insulin levels. Also, the HuUGT*28 mice had reduced Ser(P)73 PPARα immunostaining in livers and increased PPARα transcriptional activity compared with controls. A chronic but mild endogenous increase in unconjugated hyperbiliubinemia protects against hepatic steatosis through a reduction in Ser(P)73 PPARα, causing an increase in PPARα transcriptional activity.

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Comment on “Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women”

Science ◽

10.1126/science.abj1696 ◽

2021 ◽

Vol 373 (6554) ◽

pp. eabj1696

Author(s):

Charles Brenner

Keyword(s):

Placebo Group ◽

Insulin Sensitivity ◽

Randomized Trial ◽

Lipid Content ◽

Liver Fat ◽

Hepatic Lipid ◽

Nicotinamide Mononucleotide ◽

Hepatic Lipid Content

Yoshino et al. (Reports, 11 June 2021, p. 1224) have reported that nicotinamide mononucleotide (NMN) increases muscle insulin sensitivity in prediabetic women. However, the 13 women who received NMN had hepatic lipid content of 6.3 ± 1.2%, whereas the 12 in the placebo group had 14.8 ± 2.0% (P = 0.003). Given that a target of NMN is liver fat clearance, this was not an effectively randomized trial.

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Dietary sweet cherry anthocyanins attenuates diet-induced hepatic steatosis by improving hepatic lipid metabolism in mice

Nutrition ◽

10.1016/j.nut.2016.01.007 ◽

2016 ◽

Vol 32 (7-8) ◽

pp. 827-833 ◽

Cited By ~ 19

Author(s):

Haizhao Song ◽

Tao Wu ◽

Dongdong Xu ◽

Qiang Chu ◽

Dingbo Lin ◽

...

Keyword(s):

Lipid Metabolism ◽

Hepatic Steatosis ◽

Sweet Cherry ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid

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Effect of Curcumin on Growth Performance, Inflammation, Insulin level, and Lipid Metabolism in Weaned Piglets with IUGR

Animals ◽

10.3390/ani9121098 ◽

2019 ◽

Vol 9 (12) ◽

pp. 1098 ◽

Cited By ~ 1

Author(s):

Yu Niu ◽

Jintian He ◽

Yongwei Zhao ◽

Mingming Shen ◽

Lili Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Signaling Pathway ◽

Inflammatory Cytokines ◽

Slow Growth ◽

Hepatic Glycogen ◽

Lipid Levels ◽

Weaned Piglets ◽

Hepatic Lipid ◽

Pro Inflammatory Cytokines

The possible causes of intrauterine growth retardation (IUGR) might stem from placental insufficiency, maternal malnutrition, inflammation in utero, and other causes. IUGR has had an adverse influence on human health and animal production. Forty weaned piglets with normal birth weights (NBWs) or IUGR were randomly divided into four treatments groups: NBW, NC (NBW with curcumin supplementation), IUGR, and IC (IUGR with curcumin supplementation) from 26 to 50 d. Levels of cytokines, glucose, and lipid metabolism were evaluated. IUGR piglets showed slow growth during the experiment. Piglets with IUGR showed higher levels of serum pro-inflammatory cytokines, insulin resistance, and hepatic lipid accumulation. Curcumin supplementation reduced the production of serum pro-inflammatory cytokines, attenuated insulin resistance and hepatic triglyceride, and enhanced the hepatic glycogen concentrations and lipase activities of IUGR piglets. The hepatic mRNA expressions of the insulin-signaling pathway and lipogenic pathway were influenced by IUGR and were positively attenuated by diets supplemented with curcumin. In conclusion, IUGR caused slow growth, insulin resistance, and increased hepatic lipid levels. Diets supplemented with curcumin improved growth, attenuated insulin resistance, and reduced lipid levels in the liver by regulating the hepatic gene expressions of the related signaling pathway in IUGR piglets.

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A novel AMPK activator improves hepatic lipid metabolism and leukocyte trafficking in experimental hepatic steatosis

Journal of Pharmacological Sciences ◽

10.1016/j.jphs.2019.05.008 ◽

2019 ◽

Vol 140 (2) ◽

pp. 153-161

Author(s):

Xueying Peng ◽

Jin Li ◽

Minjie Wang ◽

Kai Qu ◽

Haibo Zhu

Keyword(s):

Lipid Metabolism ◽

Hepatic Steatosis ◽

Leukocyte Trafficking ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid

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LongShengZhi Capsule Reduces Established Atherosclerotic Lesions in apoE-Deficient Mice by Ameliorating Hepatic Lipid Metabolism and Inhibiting Inflammation

Journal of Cardiovascular Pharmacology ◽

10.1097/fjc.0000000000000642 ◽

2019 ◽

Vol 73 (2) ◽

pp. 105-117 ◽

Cited By ~ 8

Author(s):

Jing Ma ◽

Dan Zhao ◽

Xiaolin Wang ◽

Chuanrui Ma ◽

Ke Feng ◽

...

Keyword(s):

Lipid Metabolism ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Atherosclerotic Lesions ◽

Deficient Mice

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Disruption of the Igf2 gene alters hepatic lipid homeostasis and gene expression in the newborn mouse

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00048.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. E735-E744 ◽

Cited By ~ 3

Author(s):

Mary Frances Lopez ◽

Lingyun Zheng ◽

Ji Miao ◽

Reddy Gali ◽

Grzegorz Gorski ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Growth Factor ◽

Hepatic Steatosis ◽

Intrauterine Growth Restriction ◽

Nutritional Deficiency ◽

Growth Restriction ◽

Newborn Mouse ◽

Hepatic Lipid ◽

Intrauterine Growth

Newborns with intrauterine growth-restriction are at increased risk of mortality and life-long comorbidities. Insulin-like growth factor-II (IGF2) deficiency in humans, as well as in mice, leads to intrauterine growth restriction and decreased neonatal glycogen stores. The present study aims to further characterize the metabolic and transcriptional consequences of Igf2 deficiency in the newborn. We found that, despite being born significantly smaller than their wild-type ( Igf2+/+) littermates, brain size was preserved in Igf2 knockout ( Igf2−/−), consistent with nutritional deficiency. Histological and triglyceride analyses of newborn livers revealed that Igf2−/− mice are born with hepatic steatosis. Gene expression analysis in Igf2−/− newborn livers showed an alteration of genes known to be dysregulated in chronic caloric restriction, including the most upregulated gene, serine dehydratase. Multiple genes connected with lipid metabolism and/or hepatic steatosis were also upregulated. Ingenuity Pathway Analysis confirmed that the biological functions most altered in livers of Igf2−/− newborns are related to lipid metabolism, with the top upstream regulator predicted to be the peroxisome proliferator-activated receptor alpha, a master regulator of hepatic lipid and carbohydrate homeostasis. Together, our data indicate that Igf2 deficiency leads to a newborn phenotype strongly reminiscent of nutritional deficiency, including growth retardation, increased brain/body weight ratio, hepatic steatosis, and characteristic changes in hepatic gene expression. We propose that in addition to its growth factor proliferating functions, Igf2 may also regulate growth by altering the expression of genes that control nutrient metabolism in the newborn.

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