Hepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance

Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.

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Comprehensive fatty acid fractionation profilling in preeclampsia: a case control study with multivariable analysis

BMC Pregnancy and Childbirth ◽

10.1186/s12884-021-04313-3 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Herlambang Herlambang ◽

Anggelia Puspasari ◽

Citra Maharani ◽

Rina Nofri Enis ◽

Susan Tarawifa ◽

...

Keyword(s):

Fatty Acid ◽

Saturated Fatty Acid ◽

Reference Value ◽

Normal Pregnancy ◽

Fatty Acid Fraction ◽

Maternal Blood ◽

Acid Fraction ◽

Omega 3 ◽

Serum Fatty Acid ◽

Control Study

Abstract Background Preeclampsia is a complication during pregnancy characterised by new-onset hypertension and proteinuria that develops after 20 weeks of gestation. Dyslipidemia in pregnancy is correlated with an increased risk of preeclampsia. However, the dynamic changes in lipid metabolic product, particularly fatty acid fraction, in preeclampsia maternal circulation, are not well understood. This study aimed to investigate fatty acid fraction in preeclampsia maternal blood compared with normotensive normal pregnancy. Methods A total of 34 women who developed preeclampsia and 32 women with normotensive normal pregnancy were included in our case-control study. Maternal blood samples were collected for serum fatty acid fractions analysis and other biochemical parameters. Serum fatty acid fractions included long-chain polyunsaturated fatty acid (LCPUFA), monounsaturated fatty acid (MUFA), saturated fatty acid, and total fatty acid, measured with gas chromatography-mass spectrometry (GC-MS). The mean difference of fatty acid level was analysed using parametric and non-parametric bivariate analysis based on normality distributed data, while the risk of preeclampsia based on fatty acid fraction was analysed using a logistic regression model. Results Women with preeclampsia have lower high-density lipoprotein (53.97 ± 12.82 mg/dL vs. 63.71 ± 15.20 mg/dL, p = 0.006), higher triglyceride (284.91 ± 97.68 mg/dL vs. 232.84 ± 73.69 mg/dL, p = 0.018) than that in the normotensive group. Higher palmitoleic acid was found in women with preeclampsia compared to normotensive normal pregnancy (422.94 ± 195.99 vs. 325.71 ± 111.03 μmol/L, p = 0.037). The binary logistic regression model showed that pregnant women who had total omega-3 levels within the reference values had a higher risk of suffering preeclampsia than those with the higher reference value (odds ratio OR (95% CI): 8,5 (1.51–48.07), p = 0.015). Pregnant women who have saturated fatty acid within reference values had a lower risk for suffering preeclampsia than those in upper reference value (OR (95% CI): 0.21 (0.52–0.88), p = 0.032). Conclusion Overall, palmitoleic acid was higher in women with preeclampsia. Further analysis indicated that reference omega-3 in and high saturated fatty acid serum levels are characteristics of women with preeclampsia.

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The branched-chain fatty acids of butterfat. 2. The isolation of a multi-branched C20 saturated fatty acid fraction

Biochemical Journal ◽

10.1042/bj0500358 ◽

1952 ◽

Vol 50 (3) ◽

pp. 358-360 ◽

Cited By ~ 39

Author(s):

R. P. Hansen ◽

F. B. Shorland

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Saturated Fatty Acid ◽

Fatty Acid Fraction ◽

Acid Fraction ◽

Branched Chain Fatty Acids ◽

Branched Chain ◽

Chain Fatty Acids

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Dietary Glycotoxins Impair Hepatic Lipidemic Profile in Diet-Induced Obese Rats Causing Hepatic Oxidative Stress and Insulin Resistance

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/6362910 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

C. Neves ◽

T. Rodrigues ◽

J. Sereno ◽

C. Simões ◽

J. Castelhano ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Fatty Acid ◽

High Fat Diet ◽

De Novo ◽

Liver Lipid ◽

Lipid Fraction ◽

De Novo Lipogenesis ◽

High Fat ◽

Obese Rats

Nonalcoholic fatty liver disease (NAFLD) is caused by excessive liver lipid accumulation, but insulin resistance is specifically associated with impaired lipid saturation, oxidation, and storage (esterification), besides increased de novo lipogenesis. We hypothesized that dietary glycotoxins could impair hepatic lipid metabolism in obesity contributing to lipotoxicity-driven insulin resistance and thus to the onset of nonalcoholic steatohepatitis (NASH). In diet-induced obese rats with methylglyoxal-induced glycation, magnetic resonance spectroscopy, mass spectrometry, and gas chromatography were used to assess liver composition in fatty acyl chains and phospholipids. High-fat diet-induced obesity increased liver lipid fraction and suppressed de novo lipogenesis but did not change fatty acid esterification and saturation or insulin sensitivity. Despite a similar increase in total lipid fraction when supplementing the high-fat diet with dietary glycotoxins, impairment in the suppression of de novo lipogenesis and decreased fatty acid unsaturation and esterification were observed. Moreover, glycotoxins also decreased polyunsaturated cardiolipins and caused oxidative stress, portal inflammation, and insulin resistance in high-fat diet-induced obese rats. Dietary glycated products do not change total lipid levels in the liver of obese rats but dramatically modify the lipidemic profile, leading to oxidative stress, hepatic lipotoxicity, and insulin resistance in obesity and thus contribute to the onset of NASH.

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Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707797114 ◽

2017 ◽

Vol 114 (43) ◽

pp. E9172-E9180 ◽

Cited By ~ 21

Author(s):

Giuseppe Ferrandino ◽

Rachel R. Kaspari ◽

Olga Spadaro ◽

Andrea Reyna-Neyra ◽

Rachel J. Perry ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Secretion ◽

De Novo ◽

Endogenous Glucose Production ◽

De Novo Lipogenesis ◽

Hepatic Insulin Resistance ◽

Down Regulation ◽

Lipid Utilization ◽

Adipose Tissue Lipolysis

Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism.

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The branched-chain fatty acids of butterfat. 3. Further investigations on a multibranched C20 saturated fatty acid fraction

Biochemical Journal ◽

10.1042/bj0550662 ◽

1953 ◽

Vol 55 (4) ◽

pp. 662-663 ◽

Cited By ~ 29

Author(s):

R. P. Hansen ◽

F. B. Shorland

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Saturated Fatty Acid ◽

Fatty Acid Fraction ◽

Acid Fraction ◽

Branched Chain Fatty Acids ◽

Branched Chain ◽

Chain Fatty Acids

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Effects of Angiopoietin-Like 3 on Triglyceride Regulation, Glucose Homeostasis, and Diabetes

Disease Markers ◽

10.1155/2019/6578327 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Eliza Christopoulou ◽

Moses Elisaf ◽

Theodosios Filippatos

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

White Adipose Tissue ◽

De Novo ◽

Glucose Production ◽

De Novo Lipogenesis ◽

Metabolic Effects ◽

Hepatic Insulin Resistance ◽

Model Assessment ◽

Loss Of Function

Angiopoietin-like 3 (ANGPTL3) is a regulator of plasma triglyceride (TRG) levels due to its inhibitory action on the activity of lipoprotein lipase (LPL). ANGPTL3 is proteolytically cleaved by proprotein convertases to generate an active N-terminal domain, which forms a complex with ANGPTL8 orchestrating LPL inhibition. ANGPTL3-4-8 mouse model studies indicate that these three ANGPTL family members play a significant role in partitioning the circulating TRG to specific tissues according to nutritional states. Recent data indicate a positive correlation of ANGPTL3 with plasma glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) in insulin-resistant states. The aim of this review is to critically present the metabolic effects of ANGPTL3, focusing on the possible mechanisms involved in the dysregulation of carbohydrate homeostasis by this protein. Heterozygous and homozygous carriers of ANGPTL3 loss-of-function mutations have reduced risk for type 2 diabetes mellitus. Suggested mechanisms for the implication of ANGPTL3 in carbohydrate metabolism include the (i) increment of free fatty acids (FFAs) owing to the enhancement of lipolysis in adipose tissue, which can induce peripheral as well as hepatic insulin resistance; (ii) promotion of FFA flux to white adipose tissue during feeding, leading to the attenuation of de novo lipogenesis and decreased glucose uptake and insulin sensitivity; (iii) induction of hypothalamic LPL activity in mice, which is highly expressed throughout the brain and is associated with enhanced brain lipid sensing, reduction of food intake, and inhibition of glucose production (however, the effects of ANGPTL3 on hypothalamic LPL in humans need more clarification); and (iv) upregulation of ANGPTL4 expression (owing to the plasma FFA increase), which possibly enhances insulin resistance due to the selective inhibition of LPL in white adipose tissue leading to ectopic lipid accumulation and insulin resistance. Future trials will reveal if ANGPTL3 inhibition could be considered an alternative therapeutic target for dyslipidemia and dysglycemia.

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Lipid metabolism and adipokine levels in fatty acid-binding protein null and transgenic mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00465.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. E814-E823 ◽

Cited By ~ 78

Author(s):

Ann V. Hertzel ◽

Lisa Ann Smith ◽

Anders H. Berg ◽

Gary W. Cline ◽

Gerald I. Shulman ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Fatty Acid ◽

Transgenic Mice ◽

Fat Mass ◽

De Novo ◽

Transgenic Animals ◽

De Novo Lipogenesis ◽

Hormone Sensitive Lipase ◽

Fatty Acid Binding

Fatty acid-binding proteins (FABPs) facilitate the diffusion of fatty acids within cellular cytoplasm. Compared with C57Bl/6J mice maintained on a high-fat diet, adipose-FABP (A-FABP) null mice exhibit increased fat mass, decreased lipolysis, increased muscle glucose oxidation, and attenuated insulin resistance, whereas overexpression of epithelial-FABP (E-FABP) in adipose tissue results in decreased fat mass, increased lipolysis, and potentiated insulin resistance. To identify the mechanisms that underlie these processes, real-time PCR analyses indicate that the expression of hormone-sensitive lipase is reduced, while perilipin A is increased in A-FABP/aP2 null mice relative to E-FABP overexpressing mice. In contrast, de novo lipogenesis and expression of genes encoding lipoprotein lipase, CD36, long-chain acyl-CoA synthetase 5, and diacylglycerol acyltransferase are increased in A-FABP/aP2 null mice relative to E-FABP transgenic animals. Consistent with an increase in de novo lipogenesis, there was an increase in adipose C16:0 and C16:1 acyl-CoA pools. There were no changes in serum free fatty acids between genotypes. Serum levels of resistin were decreased in the E-FABP transgenic mice, whereas serum and tissue adiponectin were increased in A-FABP/aP2 null mice and decreased in E-FABP transgenic animals; leptin expression was unaffected. These results suggest that the balance between lipolysis and lipogenesis in adipocytes is remodeled in the FABP null and transgenic mice and is accompanied by the reprogramming of adipokine expression in fat cells and overall changes in plasma adipokines.

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