Alcohol effects on hepatic lipid metabolism

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.

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Impact of maternal undernutrition around the time of conception on factors regulating hepatic lipid metabolism and microRNAs in singleton and twin fetuses

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00600.2014 ◽

2016 ◽

Vol 310 (2) ◽

pp. E148-E159 ◽

Cited By ~ 7

Author(s):

Shervi Lie ◽

Janna L. Morrison ◽

Olivia Williams-Wyss ◽

Catherine M. Suter ◽

David T. Humphreys ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Lipid Synthesis ◽

Acid Oxidation ◽

Protein Abundance ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Maternal Undernutrition ◽

Hepatic Fatty Acid ◽

Embryo Number

We have investigated the effects of embryo number and maternal undernutrition imposed either around the time of conception or before implantation on hepatic lipid metabolism in the sheep fetus. We have demonstrated that periconceptional undernutrition and preimplantation undernutrition each resulted in decreased hepatic fatty acid β-oxidation regulators, PGC-1α ( P < 0.05), PDK2 ( P < 0.01), and PDK4 ( P < 0.01) mRNA expression in singleton and twin fetuses at 135–138 days gestation. In singletons, there was also lower hepatic PDK4 ( P < 0.01), CPT-1 ( P < 0.01), and PKCζ ( P < 0.01) protein abundance in the PCUN and PIUN groups and a lower protein abundance of PDPK-1 ( P < 0.05) in the PCUN group. Interestingly, in twins, the hepatic protein abundance of p-AMPK (Ser485) ( P < 0.01), p-PDPK-1 (Ser41) ( P < 0.05), and PKCζ ( P < 0.05) was higher in the PCUN and PIUN groups, and hepatic PDK4 ( P < 0.001) and CPT-1 ( P < 0.05) protein abundance was also higher in the PIUN twin fetus. We also found that the expression of a number of microRNAs was altered in response to PCUN or PIUN and that there is evidence that these changes may underlie the changes in the protein abundance of key regulators of hepatic fatty acid β-oxidation in the PCUN and PIUN groups. Therefore, embryo number and the timing of maternal undernutrition in early pregnancy have a differential impact on hepatic microRNA expression and on the factors that regulate hepatic fatty acid oxidation and lipid synthesis.

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Fructose-enriched diet affects hepatic lipid metabolism in young male and female rats in different ways

Archives of Biological Sciences ◽

10.2298/abs190306023n ◽

2019 ◽

Vol 71 (3) ◽

pp. 417-424 ◽

Cited By ~ 2

Author(s):

Jelena Brkljacic ◽

Natasa Velickovic ◽

Ivana Elakovic ◽

Ana Teofilovic ◽

Danijela Vojnovic-Milutinovic ◽

...

Keyword(s):

Lipid Metabolism ◽

De Novo ◽

De Novo Lipogenesis ◽

Female Rats ◽

Acid Oxidation ◽

Hepatic Lipid Metabolism ◽

Male And Female ◽

Hepatic Lipid ◽

Male And Female Rats ◽

Dietary Fructose

An increase in fructose consumption coincides with a rising incidence of metabolic disorders. Dietary fructose has been shown to affect hepatic lipid metabolism in a way that may lead to lipid deposition in the liver. In this study, we tested the hypothesis that the effects of fructose overconsumption on hepatic lipid metabolism differ between sexes. To that end we examined the effects of a high-fructose diet on the expression of key enzymes and transcription factors involved in the regulation of fatty acid oxidation and de novo lipogenesis in the liver of 12-week-old male and female Wistar rats. Immediately after weaning, the rats were subjected to a standard diet and 10% fructose solution or drinking water for 9 weeks. The fructose-enriched diet induced hypertriglyceridemia and increased hepatic de novo lipogenesis in both sexes, without lipid deposition in the liver. At the same time, visceral adiposity was observed only in female rats, while in males the treatment stimulated hepatic fatty acid oxidation. The fructose-enriched diet induced sex-specific effects on hepatic lipid metabolism in young rats. These results imply that male and female rats employ different strategies to cope with dietary fructose-related energy overload and to avoid lipid accumulation in the liver. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III41009]

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Glucagon-induced extracellular cAMP regulates hepatic lipid metabolism

Journal of Endocrinology ◽

10.1530/joe-16-0649 ◽

2017 ◽

Vol 234 (2) ◽

pp. 73-87 ◽

Cited By ~ 8

Author(s):

Sihan Lv ◽

Xinchen Qiu ◽

Jian Li ◽

Jinye Liang ◽

Weida Li ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Hepatic Steatosis ◽

Fatty Acid Oxidation ◽

Lipid Homeostasis ◽

Acid Oxidation ◽

Intracellular Camp ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Extracellular Camp

Hormonal signals help to maintain glucose and lipid homeostasis in the liver during the periods of fasting. Glucagon, a pancreas-derived hormone induced by fasting, promotes gluconeogenesis through induction of intracellular cAMP production. Glucagon also stimulates hepatic fatty acid oxidation but the underlying mechanism is poorly characterized. Here we report that following the acute induction of gluconeogenic genes Glucose 6 phosphatase (G6Pase) and Phosphoenolpyruvate carboxykinase (Pepck) expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genes Acyl-coenzyme A oxidase (Aox) and Carnitine palmitoyltransferase 1a (Cpt1a) expression via extracellular cAMP. Increase in extracellular cAMP promotes PPARα activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuates Aox and Cpt1a expression. Importantly, cAMP injection improves lipid homeostasis in fasted mice and obese mice, while inhibition of cAMP efflux deteriorates hepatic steatosis in fasted mice. Collectively, our results demonstrate the vital role of glucagon-stimulated extracellular cAMP in the regulation of hepatic lipid metabolism through AMPK-mediated PPARα activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.

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Influence of Genistein on Hepatic Lipid Metabolism in an In Vitro Model of Hepatic Steatosis

Molecules ◽

10.3390/molecules26041156 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1156

Author(s):

Lena Seidemann ◽

Anne Krüger ◽

Victoria Kegel-Hübner ◽

Daniel Seehofer ◽

Georg Damm

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Protein Expression ◽

Hepatic Steatosis ◽

In Vitro Model ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Genistein Treatment ◽

Vitro Model

Nonalcoholic fatty liver disease (NAFLD) is among the leading causes of end-stage liver disease. The impaired hepatic lipid metabolism in NAFLD is exhibited by dysregulated PPARα and SREBP-1c signaling pathways, which are central transcription factors associated with lipid degradation and de novo lipogenesis. Despite the growing prevalence of this disease, current pharmacological treatment options are unsatisfactory. Genistein, a soy isoflavone, has beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model of hepatic steatosis, primary human hepatocytes (PHHs) were incubated with free fatty acids (FFAs) and different doses of genistein. Lipid accumulation and the cytotoxic effects of FFAs and genistein treatment were evaluated by colorimetric and enzymatic assays. Changes in lipid homeostasis were examined by RT-qPCR and Western blot analyses. PPARα protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPARα protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPARα mRNA was reduced. In steatotic PHHs, genistein reversed the increase in activated SREBP-1c protein. The model realistically reflected the molecular changes in hepatic steatosis. Genistein suppressed the activation of SREBP-1c in steatotic hepatocytes, but the genistein-mediated effects on PPARα were abolished by high hepatic lipid levels.

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Altered Hepatic Lipid Metabolism Contributes to Nonalcoholic Fatty Liver Disease in Leptin-Deficient Ob/Ob Mice

Journal of Obesity ◽

10.1155/2013/296537 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 36

Author(s):

James W. Perfield ◽

Laura C. Ortinau ◽

R. Taylor Pickering ◽

Meghan L. Ruebel ◽

Grace M. Meers ◽

...

Keyword(s):

Gene Expression ◽

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

De Novo ◽

Hepatic Lipid Metabolism ◽

Nonalcoholic Fatty Liver ◽

Hepatic Lipid

Nonalcoholic fatty liver disease (NAFLD) is strongly linked to obesity, insulin resistance, and abnormal hepatic lipid metabolism; however, the precise regulation of these processes remains poorly understood. Here we examined genes and proteins involved in hepatic oxidation and lipogenesis in 14-week-old leptin-deficient Ob/Ob mice, a commonly studied model of obesity and hepatic steatosis. Obese Ob/Ob mice had increased fasting glucose, insulin, and calculated HOMA-IR as compared with lean wild-type (WT) mice. Ob/Ob mice also had greater liver weights, hepatic triglyceride (TG) content, and markers ofde novolipogenesis, including increased hepatic gene expression and protein content of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and stearoyl-CoA desaturase-1 (SCD-1), as well as elevated gene expression of PPARγand SREBP-1c compared with WT mice. While hepatic mRNA levels for PGC-1α, PPARα, and TFAM were elevated in Ob/Ob mice, measures of mitochondrial function (β-HAD activity and complete (to CO2) and total mitochondrial palmitate oxidation) and mitochondrial OXPHOS protein subunits I, III, and V content were significantly reduced compared with WT animals. In summary, reduced hepatic mitochondrial content and function and an upregulation inde novolipogenesis contribute to obesity-associated NAFLD in the leptin-deficient Ob/Ob mouse.

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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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AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms19092826 ◽

2018 ◽

Vol 19 (9) ◽

pp. 2826 ◽

Cited By ~ 21

Author(s):

Marc Foretz ◽

Patrick Even ◽

Benoit Viollet

Keyword(s):

Lipid Metabolism ◽

De Novo ◽

Fat Oxidation ◽

De Novo Lipogenesis ◽

Acid Oxidation ◽

Ampk Activation ◽

Hepatic Lipid ◽

Adenoviral Delivery ◽

Body Production

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver, achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C14]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue.

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Dietary DHA/EPA Ratio Changes Fatty Acid Composition and Attenuates Diet-Induced Accumulation of Lipid in the Liver of ApoE−/− Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/6256802 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Liang Liu ◽

Qinling Hu ◽

Huihui Wu ◽

Xiujing Wang ◽

Chao Gao ◽

...

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Lipid Metabolism ◽

Liver Disease ◽

Inflammatory Responses ◽

Elevated Serum ◽

Serum Levels ◽

Hepatic Lipid Metabolism ◽

Hepatic Lipid ◽

Fa Composition

Diets containing various docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) ratios protect against liver damage in mice fed with a high-fat diet (HFD). However, it is unclear whether these beneficial roles of DHA and EPA are associated with alterations of fatty acid (FA) composition in the liver. This study evaluated the positive impacts of n-6/n-3 polyunsaturated fatty acids (PUFAs) containing different DHA/EPA ratios on HFD-induced liver disease and alterations of the hepatic FA composition. ApoE−/− mice were fed with HFDs with various ratios of DHA/EPA (2 : 1, 1 : 1, and 1 : 2) and an n-6/n-3 ratio of 4 : 1 for 12 weeks. After treatment, the serum and hepatic FA compositions, serum biochemical parameters, liver injury, and hepatic lipid metabolism-related gene expression were determined. Our results demonstrated that dietary DHA/EPA changed serum and hepatic FA composition by increasing contents of n-6 and n-3 PUFAs and decreasing amounts of monounsaturated fatty acids (MUFAs) and the n-6/n-3 ratio. Among the three DHA/EPA groups, the DHA/EPA 2 : 1 group tended to raise n-3 PUFAs concentration and lower the n-6/n-3 ratio in the liver, whereas DHA/EPA 1 : 2 tended to raise n-6 PUFAs concentration and improve the n-6/n-3 ratio. DHA/EPA supplementation reduced the hepatic impairment of lipid homeostasis, oxidative stress, and the inflammatory responses in HFD-fed mice. The DHA/EPA 2 : 1 group had lower serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol and higher levels of adiponectin than HFD group. The DHA/EPA 1 : 2 group had elevated serum levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, without significant change the expression of genes for inflammation or hepatic lipid metabolism among the three DHA/EPA groups. The results suggest that DHA/EPA-enriched diet with an n-6/n-3 ratio of 4 : 1 may reverse HFD-induced nonalcoholic fatty liver disease to some extent by increasing n-6 and n-3 PUFAs and decreasing the amount of MUFAs and the n-6/n-3 ratio.

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