scholarly journals Paradoxical Dissociation Between Hepatic Fat Content and De Novo Lipogenesis Due to PNPLA3 Sequence Variant

2015 ◽  
Vol 100 (5) ◽  
pp. E821-E825 ◽  
Author(s):  
Rosellina M. Mancina ◽  
Niina Matikainen ◽  
Cristina Maglio ◽  
Sanni Söderlund ◽  
Nina Lundbom ◽  
...  
Keyword(s):  
De Novo ◽  
Fat Content ◽  
De Novo Lipogenesis ◽  
Liver Fat ◽  
Sequence Variant ◽  
Deuterated Water ◽  
Epidemic Disease ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Hepatic Fat

Abstract Context: Nonalcoholic fatty liver disease (NAFLD) is an emerging epidemic disease characterized by increased hepatic fat, due to an imbalance between synthesis and removal of hepatic lipids. In particular, increased hepatic de novo lipogenesis (DNL) is a key feature associated with NAFLD. The genetic variations I148M in PNPLA3 and E167K in TM6SF2 confer susceptibility to NAFLD. Objective: Here we aimed to investigate the contribution of DNL to liver fat accumulation in the PNPLA3 I148M or TM6SF2 E167K genetic determinants of NAFLD. Patients and Methods: The PNPLA3 I148M and TM6SF2 E167K were genotyped in two well-characterized cohorts of Europeans. In the first cohort (Helsinki cohort; n = 88), we directly quantified hepatic DNL using deuterated water. In the second cohort (Milan cohort; n = 63), we quantified the hepatic expression of SREBP1c that we have found previously associated with increased fat content. Liver fat was measured by magnetic resonance proton spectroscopy in the Helsinki cohort, and by histological assessment of liver biopsies in the Milan cohort. Results: PNPLA3 148M was associated with lower DNL and expression of the lipogenic transcription factor SREBP1c despite substantial increased hepatic fat content. Conclusions: Our data show a paradoxical dissociation between hepatic DNL and hepatic fat content due to the PNPLA3 148M allele indicating that increased DNL is not a key feature in all individuals with hepatic steatosis, and reinforces the contribution of decreased mobilization of hepatic triglycerides for hepatic lipid accumulation in subject with the PNPLA3 148M allele.

scholarly journals Hepatic Glucokinase Expression Is Associated with Lipogenesis and Fatty Liver in Humans

2011 ◽  
Vol 96 (7) ◽  
pp. E1126-E1130 ◽  
Author(s):  
Andreas Peter ◽  
Norbert Stefan ◽  
Alexander Cegan ◽  
Mareike Walenta ◽  
Silvia Wagner ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Human Liver ◽  
De Novo ◽  
Fat Content ◽  
De Novo Lipogenesis ◽  
Liver Fat ◽  
Liver Fat Content ◽  
Human Liver Biopsies ◽  
Triglyceride Content ◽  
Liver Biopsies

Abstract Background/Aims: Glucokinase (GCK) phosphorylates glucose to form glucose 6-phosphate and thereby regulates hepatic glucose disposal and activates hepatic lipogenesis. Hepatic GCK activity is regulated on the level of GCK mRNA expression and by the inhibitory glucokinase regulatory protein. In this study, we aimed to investigate the relation between GCK mRNA expression and markers of lipogenesis as well as liver fat content in human liver biopsies. Additionally, we investigated whether genetic variation in the liver specific GCK promoter determines liver fat content in humans. Methods: Hepatic mRNA expression and liver triglyceride content was analyzed in 50 human liver biopsies. In a second cohort of 330 individuals, liver fat was precisely measured by 1H magnetic resonance spectroscopy. Results: Hepatic GCK mRNA expression is associated with triglyceride content in human liver biopsies (r = 0.50, P = 0.0002). Furthermore, hepatic GCK mRNA expression is associated with lipogenic gene expression (fatty acid synthase, r = 0.49, P = 0.0003; acetyl-coenzyme A carboxylase-α, r = 0.44, P = 0.0015, and acetyl-coenzyme A carboxylase-β, r = 0.48, P = 0.0004) and the de novo lipogenesis index (r = 0.36, P = 0.01). In support of these findings, the single-nucleotide polymorphism rs2041547 in the liver-specific GCK promoter is associated with liver fat content in prediabetic individuals (P = 0.047). Conclusions: In this study, we demonstrate for the first time that GCK mRNA expression is associated with markers of de novo lipogenesis and liver triglyceride content in humans. This suggests that increased GCK activity may induce fatty liver and its metabolic and hepatic consequences in humans. Thus, the widely used approach to nonspecifically activate β-cell and hepatic GCK to treat diabetes mellitus is therefore questionable and may cause serious side effects.

scholarly journals The relationship between Lipocalin-2 level and hepatic steatosis in obese patients with NAFLD after bariatric surgery

2022 ◽  
Vol 21 (1) ◽  
Author(s):  
Jiaqi Chen ◽  
Shihui Lei ◽  
Yueye Huang ◽  
Xiaojuan Zha ◽  
Lei Gu ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Fat Content ◽  
Liver Fat ◽  
Obese Patients ◽  
Lipocalin 2 ◽  
Liver Fat Content ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Fat ◽  
Relationship Of ◽  
The Relationship

Abstract Background Lipocalin-2 (LCN2) has a critical effect on obesity as well as its associated comorbidities. The present study focused on analyzing serum LCN2 levels of obese patients with nonalcoholic fatty liver disease (NAFLD) and on determining relationship of hepatic steatosis improvement with LCN2 levels after laparoscopic sleeve gastrectomy (LSG). Methods This work enrolled ninety patients with obesity and NAFLD. Twenty-three of them underwent LSG. Anthropometric and biochemical parameters and serum LCN2 levels were determined at baseline and those at 6-month post-LSG. Controlled attenuation parameter (CAP) measured by FibroScan was adopted for evaluating hepatic steatosis. Results Among severe obesity patients, serum LCN2 levels were significantly increased (111.59 ± 51.16 ng/mL vs. 92.68 ± 32.68 ng/mL, P = 0.035). The CAP value was higher indicating higher liver fat content (360.51 ± 45.14 dB/m vs. 340.78 ± 45.02 dB/m, P = 0.044). With regard to surgical patients, liver function, glucose, and lipid levels were significantly improved after surgery. Serum LCN2 levels significantly decreased (119.74 ± 36.15 ng/mL vs. 87.38 ± 51.65 ng/mL, P = 0.001). Decreased CAP indicated a significant decrease in liver fat content (358.48 ± 46.13 dB/m vs. 260.83 ± 69.64 dB/m, P < 0.001). The decrease in LCN2 levels was significantly related to the reduced hepatic fat content and improvement in steatosis grade after adjusting for gender, age, and BMI decrease. Conclusions Serum LCN2 levels are related to obesity and NAFLD. The decreased serum LCN2 levels could be an indicator of hepatic steatosis improvement.

scholarly journals The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 36-44 ◽  
Author(s):  
Derek M. Erion ◽  
Violetta Popov ◽  
Jennifer J. Hsiao ◽  
Daniel Vatner ◽  
Kisha Mitchell ◽  
...  
Keyword(s):  
De Novo ◽  
Binding Protein ◽  
De Novo Lipogenesis ◽  
Sprague Dawley ◽  
Inherited Disorders ◽  
Response Element ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Triglyceride Secretion ◽  
Element Binding Protein

By 2030, nearly half of Americans will have nonalcoholic fatty liver disease. In part, this epidemic is fueled by the increasing consumption of caloric sweeteners coupled with an innate capacity to convert sugar into fat via hepatic de novo lipogenesis. In addition to serving as substrates, monosaccharides also increase the expression of key enzymes involved in de novo lipogenesis via the carbohydrate response element-binding protein (ChREBP). To determine whether ChREBP is a potential therapeutic target, we decreased hepatic expression of ChREBP with a specific antisense oligonucleotide (ASO) in male Sprague-Dawley rats fed either a high-fructose or high-fat diet. ChREBP ASO treatment decreased plasma triglyceride concentrations compared with control ASO treatment in both diet groups. The reduction was more pronounced in the fructose-fed group and attributed to decreased hepatic expression of ACC2, FAS, SCD1, and MTTP and a decrease in the rate of hepatic triglyceride secretion. This was associated with an increase in insulin-stimulated peripheral glucose uptake, as assessed by the hyperinsulinemic-euglycemic clamp. In contrast, ChREBP ASO did not alter hepatic lipid content or hepatic insulin sensitivity. Interestingly, fructose-fed rats treated with ChREBP ASO had increased plasma uric acid, alanine transaminase, and aspartate aminotransferase concentrations. This was associated with decreased expression of fructose aldolase and fructokinase, reminiscent of inherited disorders of fructose metabolism. In summary, these studies suggest that targeting ChREBP may prevent fructose-induced hypertriglyceridemia but without the improvements in hepatic steatosis and hepatic insulin responsiveness.

scholarly journals Contribution of de novo lipogenesis to the progression of nonalcoholic fatty liver disease

2020 ◽  
Author(s):  
◽  
Majid Mufaqam Syed Abdul
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
Liver Enzymes ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Liver Fat ◽  
Percent Reduction ◽  
Nonalcoholic Fatty Liver

This dissertation is focused on understanding the biochemical pathway of de novo lipogenesis (DNL) in humans and how changes in DNL can alter disease states, particularly nonalcoholic fatty liver disease (NAFLD). This document's first chapter presents a review of the literature, while the second chapter focuses on investigating the contribution of DNL to the progression of NAFLD. The main outcome of this study was that as disease severity progressed, hepatic DNL increased in a stepwise fashion until fibrosis was significant, at which time DNL was found to be reduced. Conclusions from isotopic labeling of liver were mirrored by data from protein and gene expression studies which pointed toward mechanisms of promoting both fat storage and decreased fatty acid oxidation. In the third chapter, data are presented on the effects of pharmacological inhibition of DNL, which lowered both liver fat (from 11.8 [percent] to 10.3 [percent]) and liver enzymes (from 29 to 22 U/L). In this study, different subjects received different doses (50, 100, and 15 mg/d) and within the high dose group, DNL was reduced maximally by 75 [percent] which resulted in a 5 [percent] reduction in liver fat and a 36 [percent] reduction in liver enzymes. Lastly, this dissertation's fourth chapter presents data from an investigation in which acute overconsumption of food and alcohol increased liver fat only in individuals whose DNL was stimulated by this treatment but not in individuals with unchanged DNL. The variability in response between subjects was surprising and suggested that for some people, overconsumption of carbohydrates may have greater lipogenic effects than excess alcohol. Future studies should identify the factors that govern this response. In summary, the combined data from these studies highlight the significance of the DNL pathway in promoting increased fat storage in the liver. This conclusion is supported by independent observations of both the negative effects of increased DNL on the liver and the benefits of reducing flux through this pathway to improve liver health. Both dietary and pharmacologic approaches to reduce DNL should be the focus of future treatment of NAFLD.

scholarly journals Association between diet quality indicators and nonalcoholic fatty liver disease: The FLiO study

2020 ◽  
Vol 79 (OCE2) ◽  
Author(s):  
Cristina Galarregui ◽  
M. Angeles Zulet ◽  
Bertha Araceli Marin-Alejandre ◽  
Irene Cantero ◽  
Nora Goodwin ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Diet Quality ◽  
Fatty Liver Disease ◽  
Fat Content ◽  
Liver Fat ◽  
Liver Fat Content ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Fat

AbstractIntroductionDietary components are contributing factors in the development of Nonalcoholic fatty liver disease (NAFLD). The glycaemic index (GI), glycaemic load (GL) and total antioxidant capacity (TAC) have been considered potential dietary tools influencing diet–disease relationships. The aim of this study was to evaluate associations of the dietary GI, GL, TAC and insulin resistance (IR) condition with hepatic fat in NAFLD adults.Material and methods: 112 overweight/obese adults with NAFLD (age: 50.8 ± 9 years old) were included in the trial. Dietary intake was assessed by a validated 137-item food frequency questionnaire (FFQ). Anthropometric, glycemic and lipid profiles, fatty liver quantification by magnetic resonance imaging (MRI) and IR measured by the Homeostatic Model Assessment of IR (HOMA-IR) were assessed at baseline. This study was registered as FLiO: Fatty Liver in Obesity study; NCT03183193.Results: The median of liver fat content by MRI was 6.4 (3.8–10.9) in the recruited population. Participants with higher liver fat content showed significantly increased values of glucose, insulin, HbA1c and HOMA-IR than those with lower liver fat content (p < 0.05). Correlation analyses revealed relevant positive associations of hepatic fat with GI (r = 0.17; p = 0.077) and GL (r = 0.19; p = 0.047). Also, a negative association between liver fat content and TAC (r = -0.22; p = 0.023) was found. Linear regression analyses were used to examine the associations of hepatic fat and dietary quality indicators as well as IR adjusted for potential confounders (sex, age and physical activity). The final models showed that HOMA-IR, GI, GL and TAC were able to explain between 22.4 and 22.8 % (p < 0.001) of the variability of liver fat content.DiscussionThe pathophysiology of NAFLD is thought to be associated with dietary determinants that contribute to metabolic dysregulation such as IR, ectopic liver fat deposition and hepatic damage. In accordance with other authors, we suggest that monitoring GI, GL and TAC may be useful approaches for the dietary treatment of NAFLD since they are related to hepatic fat. Additionally, it is important to highlight the essential role of IR in NAFLD as a key mediator in the development of NAFLD. Certainly, findings of the present study revealed a significant association of hepatic fat accumulation and IR.In summary, GI, GL and TAC are potential markers of diet quality, with an impact on susceptible population at hepatic risk.

scholarly journals Concepts and Treatment Approaches in Nonalcoholic Fatty Liver Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Dina L. Halegoua-De Marzio ◽  
Jonathan M. Fenkel
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Imaging Techniques ◽  
De Novo Lipogenesis ◽  
Central Adiposity ◽  
Preventative Care ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of adults and is the most common liver disease in Western nations. NAFLD is associated with central adiposity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, and cardiovascular disease. It encompasses the entire spectrum of fatty liver diseases from simple steatosis to nonalcoholic steatohepatitis (NASH) with lobular/portal inflammation, hepatocellular necrosis, and fibrosis. Of those who develop NASH, 15–25% will progress to end stage liver disease and hepatocellular carcinoma over 10–20 years. Its pathogenesis is complex, and involves a state of lipid accumulation due to increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, and increased incidence of de novo lipogenesis. Plasma aminotransferases and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for definitive diagnosis. Many new plasma biomarkers and imaging techniques are now available that should improve the ability to diagnose NAFLD noninvasively Due to its complexity and extrahepatic complications, treatment of NAFLD requires a multidisciplinary approach with excellent preventative care, management, and treatment. This review will evaluate our current understanding of NAFLD, with a focus on existing therapeutic approaches and potential pharmacological developments.

Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification

1998 ◽  
Vol 274 (2) ◽  
pp. E321-E327 ◽  
Author(s):  
Frederique Diraison ◽  
Michel Beylot
Keyword(s):  
Turnover Rate ◽  
De Novo ◽  
Plasma Free Fatty Acid ◽  
Normal Subjects ◽  
De Novo Lipogenesis ◽  
Deuterated Water ◽  
Extrahepatic Tissues ◽  
Almost All ◽  
State 1

To measure 1) the contribution of hepatic de novo lipogenesis (DNL) and plasma free fatty acid (FFA) reesterification to plasma triglyceride (TG) secretion, and 2) the role of oxidation and hepatic and extrahepatic reesterification in FFA utilization, five normal subjects drank deuterated water and were infused (postabsorptive state) with [1-13C]palmitate and [1,2,3-2H5]glycerol. Total lipid oxidation (Lox) was measured by indirect calorimetry. FFA oxidation (2.76 ± 0.65 μmol ⋅ kg−1 ⋅ min−1) accounted for 45% of FFA turnover rate (Rt) (1.04 μmol ⋅ kg−1 ⋅ min−1) and 91% of Lox; FFA reesterification was 3.27 ± 0.54 μmol ⋅ kg−1 ⋅ min−1. Fractional and absolute TG Rt were 0.21 ± 0.02 h−1 and 0.11 ± 0.05 μmol ⋅ kg−1 ⋅ min−1. DNL accounted for 3.9 ± 0.9% of TG secretion, and hepatic FFA reesterification accounted for 49.4 ± 5.7%; this last process represented a utilization of FFA of 0.16 ± 0.02 μmol ⋅ kg−1 ⋅ min−1. We conclude that, in the postabsorptive state, 1) DNL and FFA reesterification account for only 50–55% of TG secretion, the remaining presumably being provided by stored lipids or lipoproteins taken up by liver, 2) most reesterification occurs in extrahepatic tissues, and 3) oxidation and reesterification each contribute about one-half to FFA utilization; FFA oxidation accounts for almost all Lox.

scholarly journals Regular exercise potentiates energetically expensive hepatic de novo lipogenesis during early weight regain

2019 ◽  
Vol 317 (5) ◽  
pp. R684-R695
Author(s):  
David M. Presby ◽  
L. Allyson Checkley ◽  
Matthew R. Jackman ◽  
Janine A. Higgins ◽  
Kenneth L. Jones ◽  
...  
Keyword(s):  
Weight Loss ◽  
Energy Expenditure ◽  
De Novo ◽  
Energy Gap ◽  
Cholesterol Biosynthesis ◽  
Density Lipoprotein ◽  
De Novo Lipogenesis ◽  
Positive Energy ◽  
Hepatic Expression ◽  
Expression Of Genes

Exercise is a potent facilitator of long-term weight loss maintenance (WLM), whereby it decreases appetite and increases energy expenditure beyond the cost of the exercise bout. We have previously shown that exercise may amplify energy expenditure through energetically expensive nutrient deposition. Therefore, we investigated the effect of exercise on hepatic de novo lipogenesis (DNL) during WLM and relapse to obesity. Obese rats were calorically restricted with (EX) or without (SED) treadmill exercise (1 h/day, 6 days/wk, 15 m/min) to induce and maintain weight loss. After 6 wk of WLM, subsets of WLM-SED and WLM-EX rats were allowed ad libitum access to food for 1 day to promote relapse (REL). An energy gap-matched group of sedentary, relapsing rats (REL-GM) were provided a diet matched to the positive energy imbalance of the REL-EX rats. During relapse, exercise increased enrichment of hepatic DN-derived lipids and induced hepatic molecular adaptations favoring DNL compared with the gap-matched controls. In the liver, compared with both REL-SED and REL-GM rats, REL-EX rats had lower hepatic expression of genes required for cholesterol biosynthesis; greater hepatic expression of genes that mediate very low-density lipoprotein synthesis and secretion; and greater mRNA expression of Cyp27a1, which encodes an enzyme involved in the biosynthesis of bile acids. Altogether, these data provide compelling evidence that the liver has an active role in exercise-mediated potentiation of energy expenditure during early relapse.

Loss of regulation of lipogenesis in the Zucker diabetic (ZDF) rat

2000 ◽  
Vol 279 (2) ◽  
pp. E425-E432 ◽  
Author(s):  
W.-N. Paul Lee ◽  
Sara Bassilian ◽  
Shu Lim ◽  
Laszlo G. Boros
Keyword(s):  
High Fat Diet ◽  
Leptin Receptor ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Chain Elongation ◽  
Deuterated Water ◽  
High Fat ◽  
Macronutrient Composition ◽  
Zdf Rat

We present here a study on the role of leptin in the regulation of lipogenesis by examining the effect of dietary macronutrient composition on lipogenesis in the leptin receptor-defective Zucker diabetic fatty rat (ZDF) and its lean litter mate (ZL). Animals were pair fed two isocaloric diets differing in their fat-to-carbohydrate ratio providing 10 and 30% energy as fat. Lipogenesis was measured in the rats using deuterated water and isotopomer analysis. From the deuterium incorporation into plasma palmitate, stearate, and oleate, we determined de novo synthesis of palmitate and synthesis of stearate by chain elongation and of oleate by desaturation. Because the macronutrient composition and the caloric density were controlled, changes in de novo lipogenesis under these dietary conditions represent adaptation to changes in the fat-to-carbohydrate ratio of the diet. De novo lipogenesis was normally suppressed in response to the high-fat diet in the ZL rat to maintain a relatively constant amount of lipids transported. The ZDF rat had a higher rate of lipogenesis, which was not suppressed by the high-fat diet. The results suggest an important hormonal role of leptin in the feedback regulation of lipogenesis.

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