Free Fatty Acid Flux Research Articles

Effects of High Intensity Statin Therapy in the Treatment of Diabetic Dyslipidemia in Patients with Coronary Artery Disease.

Diabetic dyslipidemia has specifics that differ from dyslipidemia in patients without diabetes, which contributes to accelerated atherosclerosis equally as dysglycemia. The aim of this study was to deduce the interdependence of diabetic dyslipidemia and cardiovascular diseases (CVD), therapeutic strategies and the risk of diabetes development with statin therapy. We conducted a literature review of English articles through PubMed, PubMed Central and Cochrane, on the role of diabetic dyslipidemia in atherosclerosis, the antilipemic treatment with statins, and the role of statin therapy in newly developed diabetes, by using key words: atherosclerosis, diabetes mellitus, diabetic dyslipidemia, CVD, statins, nicotinic acid, fibrates, PCSK9 inhibitors. hyperglycemia and dyslipidemia cannot be treated separately in patients with diabetes. It seems that dyslipidemia plays one of the key roles in the development of atherosclerosis. High levels of TG, decreased levels of HDL-C and increased levels of small dense LDL- C particles in the systemic circulation are the most specific attributes of diabetic dyslipidemia, all of which originate from an inflated flux of free fatty acids occurring due to the preceding resistance to insulin, and exacerbated by elevated levels of inflammatory adipokines. Statins are a fundamental treatment for diabetic dyslipidemia, both for dyslipidemia and for CVD prevention. The use of statin treatment with high intensity is endorsed for all diabetes-and-CVD patients, while a moderate - intensity treatment can be applied to patients with diabetes, having additional risk factors for CVD. Statins alone are thought to possess a small, although of statistical significance, risk of incident diabetes, outweighed by their benefits. As important as hyperglycemia and glycoregulation are in CVD development in patients with diabetes, diabetic dyslipidemia plays an even more important role. Statins remain the cornerstone of antilipemic treatment in diabetic dyslipidemia, and their protective effects in CVD progression overcome the risk of statin- associated incident diabetes.

Tetrahydrocurcumin ameliorates free fatty acid-induced hepatic steatosis and improves insulin resistance in HepG2 cells

Elevated levels of free fatty acids (FFAs) in the liver, resulting from either increased lipolysis or imbalanced FFAs flux, is a key pathogenic factor of hepatic steatosis. This study was conducted to examine the therapeutic effect of tetrahydrocurcumin (THC), a naturally occurring curcuminoid and a metabolite of curcumin, on oleic acid (OA)-induced steatosis in human hepatocellular carcinoma cells and to elucidate the underlying mechanism. HepG2 cells were incubated with OA to induce steatosis, and then treated with various concentrations of THC. The results showed that THC treatment significantly decreased lipid accumulation in OA-treated HepG2 cells, possibly, by inhibiting the expression of the lipogenic proteins, sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid synthase (FAS), and fatty acid-binding protein 4 (FABP4). Moreover, THC attenuated OA-induced hepatic lipogenesis in an adenosine monophosphate–activated protein kinase (AMPK)-dependent manner, which was reversed by pretreatment with an AMPK inhibitor. THC promoted lipolysis and upregulated the expression of genes involved in β-oxidation. Glucose uptake and insulin signaling impaired in HepG2 cells incubated with OA were abated by THC treatment, including phosphorylation of the insulin receptor substrate 1 (IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt and downstream signaling pathways, forkhead box protein O1 (FOXO1) and glycogen synthase kinase 3 β (GSK3β), which are involved in gluconeogenesis and glycogen synthesis, respectively. Altogether, these results demonstrated the novel therapeutic benefit of THC against hepatic steatosis and, consequently, a potential treatment for non-alcoholic fatty liver disease (NAFLD).

Short-Term Microbiota Manipulation and Forearm Substrate Metabolism in Obese Men: A Randomized, Double-Blind, Placebo-Controlled Trial

Objective: To investigate the impact of gut microbiota manipulation on fasting and postprandial skeletal muscle metabolism in humans. Methods: 40 obese, insulin-resistant males were randomized to amoxicillin (broad-spectrum antibiotic), vancomycin (narrow-spectrum antibiotic), or placebo (7 days, 1,500 mg/day). Before and after treatment, forearm blood flow and metabolite fluxes across forearm muscle were measured under fasting and postprandial (high-fat mixed-meal) conditions. Results: Vancomycin decreased bacterial diversity, reduced the abundance of Gram-positive Firmicutes, and increased the abundance of Gram-negative Proteobacteria, whereas amoxicillin did not affect microbial composition. Neither vancomycin nor amoxicillin treatment affected fasting and postprandial plasma glucose, free fatty acid (FFA), triacylglycerol (TAG), glycerol, lactate, and insulin concentrations or forearm blood flow. Fasting and postprandial net forearm muscle glucose uptake and the release of lactate were not significantly altered by antibiotic treatment as compared to placebo. Finally, antibiotic treatment did not change fasting and postprandial glycerol, FFA, and TAG fluxes across forearm muscle. Conclusion: The present study demonstrates that short-term antibiotic treatment has no effects on fasting and postprandial forearm substrate metabolism and blood flow in obese men with impaired glucose metabolism. These data suggest that short-term strategies targeting the gut microbiota to improve metabolic health may not be effective in obese humans.

Advances in the pathogenesis of non alcoholic fatty liver disease

Non alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, and the most common liver disease. Its more aggressive form is the non alcoholic steatohepatitis. Multiple genetic and environmental factors lead to the accumulation of triglicerides and the inflammatory cascade. High fat diet, obesity, adipocyte dysfunction with cytokine production, insulin resistance and increased lipolysis with free fatty acid flux into the liver - all are the drivers of liver cell injury. Activation of inflammasome by damage- or pathogen-associated molecular patterns results in "steril inflammation" and immune response, while the hepatic stellate cells and progenitor cells lead to fibrogenesis. Small intestinal bacterial overgrowth and gut dysbiosis are also of pivotal importance in the inflammation. Among the susceptible genetic factors, mutations of patatin-like phospholipase domain containing 3 and the transmembrane 6 superfamily 2 genes play a role in the development and progression of the disease, similarly as do epigenetic regulators such as microRNAs and extracellular vesicles. Better understanding of the pathogenesis of non alcoholic fatty liver disease may identify novel therapeutic agents that improve the outcome of the disease. Orv Hetil. 2017; 158(23): 882-894.

Dyslipidemia and associated factors among diabetic patients attending Durame General Hospital in Southern Nations, Nationalities, and People's Region.

BackgroundDiabetes mellitus is a group of metabolic disorders that are caused by deficiency in insulin secretion or the decreased ability of insulin to act effectively on target tissues, particularly muscle, liver, and fat. As a result of insulin resistance in the target tissues, particularly in the adipocytes, free fatty acid flux is increased, leading to increased lipid synthesis in hepatocytes, which is responsible for diabetic dyslipidemia.ObjectiveThe objective of this study was to determine the prevalence and associated factors of dyslipidemia among diabetic patients in Durame General Hospital in Kembata Tembaro zone.MethodsA cross-sectional study was conducted from September 2015 to April 2016. In total, 224 subjects were involved in the study by using convenient sampling techniques. Face-to-face interview–administered questionnaire was used to collect sociodemographic data and other possible clinical data associated with the prevalence of dyslipidemia. Fasting venous blood specimens were collected to assess serum lipid profiles. Blood pressure (BP), weight, height, and waist circumference were measured.ResultsThe prevalence of dyslipidemia was 65.6%. Individual lipid abnormality of elevated LDL-C, TC, TG, and reduced HDL-C were identified in 43.8%, 23.7%, 40.6%, and 41.9% of study subjects, respectively. The prevalence of dyslipidemia was significantly associated with high BP, high body mass index, aging, and longer duration of diabetes mellitus.ConclusionHigh prevalence of dyslipidemia was found among diabetic patients in the study area. Therefore, a compressive mechanism is required to screen, treat, and prevent dyslipidemia.

Activation of β3-adrenoceptors increases in vivo free fatty acid uptake and utilization in brown but not white fat depots in high-fat-fed rats.

Activation of brown adipose tissue (BAT) and browning of white adipose tissue (WAT) present potential new therapies for obesity and type 2 diabetes. Here, we examined the effects of β3-adrenergic stimulation on tissue-specific uptake and storage of free fatty acids (FFA) and its implications for whole body FFA metabolism in diet-induced obese rats using a multi-radiotracer technique. Male Wistar rats were high fat-fed for 12 wk and administered β3-agonist CL316,243 (CL, 1 mg·kg-1·day-1) or saline via osmotic minipumps during the last 3 wk. The rats were then fasted and acutely infused with a tracer mixture ([14C]palmitate and the partially metabolized R-[3H]bromopalmitate) under anesthesia. CL infusion decreased body weight gain and fasting plasma glucose levels. While core body temperature was unaffected, infrared thermography showed an increase in tail heat dissipation following CL infusion. Interestingly, CL markedly increased both FFA storage and utilization in interscapular and perirenal BAT, whereas the flux of FFA to skeletal muscle was decreased. In this rat model of obesity, only sporadic populations of beige adipocytes were detected in the epididymal WAT depot of CL-infused rats, and there was no change in FFA uptake or utilization in WAT following CL infusion. In summary, β3-agonism robustly increased FFA flux to BAT coupled with enhanced utilization. Increased BAT activation most likely drove the increased tail heat dissipation to maintain thermostasis. Our results emphasize the quantitative role of brown fat as the functional target of β3-agonism in obesity.

A System for In Vivo Imaging of Hepatic Free Fatty Acid Uptake

Alterations in hepatic free fatty acid (FFA) uptake and metabolism contribute to the development of prevalent liver disorders such as hepatosteatosis. However, detecting dynamic changes in FFA uptake by the liver in live model organisms has proven difficult. To enable noninvasive real-time imaging of FFA flux in the liver, we generated transgenic mice with liver-specific expression of luciferase and performed bioluminescence imaging with an FFA probe. Our approach enabled us to observe the changes in FFA hepatic uptake under different physiological conditions in live animals. By using this method, we detected a decrease in FFA accumulation in the liver after mice were given injections of deoxycholic acid and an increase after they were fed fenofibrate. In addition, we observed diurnal regulation of FFA hepatic uptake in living mice. Our imaging system appears to be a useful and reliable tool for studying the dynamic changes in hepatic FFA flux in models of liver disease.

A study of serum magnesium and dyslipidemia in type 2 diabetes mellitus patients

Background: Type 2 diabetes is a heterogeneous metabolic disease characterised by insulin resistance in peripheral tissue together with impaired insulin secretion. It affects more than 285 million peoples worldwide and estimated that it will affect more than 438 million by the year 2030. It is the leading cause of morbidity and mortality. Magnesium is an important intracellular cation. Hypomagnesaemia is associated with diabetes. Dyslipidemia is seen in Diabetes mellitus. Objectives: To estimate serum magnesium and lipid profile in type 2 diabetes mellitus patients and controls. To correlate serum Magnesium level with lipid profile in type 2 diabetes mellitus patients. Materials & methods: A total of 100 subjects were included, out of which 50 were cases and 50 were controls. Fasting blood sugar (FBS), serum magnesium and lipid profile were measured. Data was statistically analyzed using SPSS 17thversion. Results: There was statistical significant difference of serum Magnesium levels 1.56mg/dI due to hyperglycemia induced osmotic diuresis , Total cholesterol (TC), Triglycerides, Low density lipoprotein(LDL) and High density lipoprotein(HDL) due to increased flux of free fatty acids to liver secondary to insulin resistance was observed in Type 2 diabetes when compared with healthy controls. Significant negative correlation was observed between serum magnesium with Fasting blood glucose, TC, Triglycerides and LDL. Significant positive correlation was observed between serum magnesium and HDL levels. Conclusion: Hypomagnesaemia has role in perturbation of lipid metabolism in diabetics. Keywords: Fasting Blood Sugar, Dyslipidemia, Serum Magnesium

Myocardial Fat Accumulation Is Independent of Measures of Insulin Sensitivity.

Myocardial steatosis, an independent predictor of diastolic dysfunction, is frequently present in type 2 diabetes mellitus. High free fatty acid flux, hyperglycemia, and hyperinsulinemia may play a role in myocardial steatosis. There are no prior studies examining the relationship between insulin sensitivity (antilipolytic and glucose disposal actions of insulin) and cardiac steatosis. Using a cross-sectional study design of individuals with and without metabolic syndrome (MetSyn), we examined the relationships between cardiac steatosis and the sensitivity of the antilipolytic and glucose disposal actions of insulin. Pericardial fat (PF) volume, intramyocardial and hepatic fat (MF and HF) content, visceral fat (VF) and sc fat content were assessed by magnetic resonance imaging in 77 subjects (49 without MetSyn and 28 with MetSyn). In a subset of the larger cohort (n = 52), peripheral insulin sensitivity index (SI) and adipocyte insulin sensitivity (Adipo-SI) were determined from an insulin-modified frequently sampled iv glucose tolerance test. The Quantitative Insulin Sensitivity Check Index was used as a surrogate for hepatic insulin sensitivity. Individuals with the MetSyn had significantly higher body mass index, total body fat, and MF, PF, HF, and VF content. HF and VF, but not MF, were negatively correlated with the Quantitative Insulin Sensitivity Check Index, Adipo-SI, and SI. Stepwise regression revealed that waist circumference and serum triglyceride levels independently predicted MF and PF, respectively. Adipo-SI and serum triglyceride levels independently predict HF. Myocardial steatosis is unrelated to hepatic, adipocyte, or peripheral insulin sensitivity. Although it is frequently observed in insulin-resistant subjects, further studies are necessary to identify and delineate pathogenic mechanisms that differentially affect cardiac and hepatic steatosis.

Effects of increased free fatty acid availability on adipose tissue fatty acid storage in men.

A portion of free fatty acids (FFA) released from adipose tissue lipolysis are re-stored in adipocytes via direct uptake. Rates of direct adipose tissue FFA storage are much greater in women than men, but women also have greater systemic FFA flux and more body fat. We tested the hypotheses that experimental increases in FFA in men would equalize the rates of direct adipose tissue FFA storage in men and women. We used a lipid emulsion infusion to raise FFA in men to levels seen in post-absorptive women. Direct FFA storage (μmol · kg fat(-1) · min(-1)) rates in abdominal and femoral fat was assessed using stable isotope tracer infusions to measure FFA disappearance rates and an iv FFA radiotracer bolus/timed biopsy. These studies were performed in a Clinical Research Center. Data from 13 non-obese women was compared with that from eight obese and eight non-obese men. The men received a lipid emulsion infusion to raise FFA. We measured the rates of direct FFA storage in abdominal and femoral adipose tissue. The three groups were similar in age and FFA flux by design; obese men had similar body fat percentage as non-obese women. Despite matching for FFA concentrations and flux, FFA storage per kg abdominal (P < .01) and femoral (P < .001) fat was less in both lean and obese men than in non-obese women. Abdominal FFA storage rates were correlated with proteins/enzymes in the FFA uptake/triglyceride synthesis pathway in men. The lesser rates of direct FFA adipose tissue in men compared with women cannot be explained by reduced FFA availability.

CrossTalk opposing view: De novo capillary recruitment in healthy muscle is not necessary to explain physiological outcomes.

Several thousand capillaries are small enough to fit comfortably on the period at the end of this sentence and yet, within skeletal muscle, thousands of miles of capillaries combine to provide a vast surface, some hundreds of square metres, that is essential for blood–myocyte flux of O2, glucose and free fatty acids. As dictated by muscle metabolic demands and a complex array of neural, humoral and local controllers, muscular arterioles function as ‘gatekeepers’, regulating capillary red blood cell (RBC) and plasma flow. The issue considered here is whether or not most capillaries support RBC and/or plasma flux in resting skeletal muscle. If such is the case, this dismisses de novo recruitment of capillaries as a requirement for increased blood–myocyte flux either at rest or during muscle contractions. Resolution of this problem is fundamental to understanding muscle metabolic function in health and the mechanistic bases for dysfunction in diseases such as diabetes, sepsis and heart failure (Lemkes et al. 2012; Poole et al. 2012; Eskens et al. 2013).

A Lifetime on the Hips: Programming Lower-Body Fat to Protect Against Metabolic Disease

In the 60 years since Vague (1) described that an “android” pattern of adipose tissue (AT) distribution was associated with diabetes, atherosclerosis, gout, and kidney stones, many of the physiological mechanisms underlying this relationship have been illuminated. To date, most of the effort has been directed at understanding how accumulation of intra-abdominal fat, also known as visceral AT (VAT), promotes insulin resistance (IR). IR is the common defect underlying glucose intolerance, central obesity, dyslipidemia, and hypertension. This phenotypic cluster, called the metabolic syndrome, is associated with a doubling of cardiovascular disease risk and a fivefold increased risk of type 2 diabetes (2). VAT is likely to promote IR in several ways. Enlarged adipocytes in VAT were originally thought to promote hepatic, and eventually systemic, IR via increased portal free fatty acid (FFA) flux (3). Other factors are likely to be involved, however, because although FFA flux from VAT does increase in obesity, it is not the major determinant of portal FFA concentrations (4). In obesity, VAT also may contribute to IR via alterations in its secreted products (adipokines), as well as proinflammatory molecules such as tumor necrosis factor-α, interleukin-6 (IL-6), C-reactive protein (CRP), and monocyte chemoattractant protein-1 (MCP-1) (5). Independently of VAT, parallel studies have established that a gynoid pattern of AT distribution, characterized by greater amounts of subcutaneous AT (SAT) in the lower body, is associated with improved glucose tolerance and lipid profile and that this fat pattern may protect against cardiovascular disease (6,7). These protective effects often vary with sex, but …

Do the epidemiology, physiological mechanisms and characteristics of hepatocellular carcinoma in HIV-infected patients justify specific screening policies?

Reducing the incidence of hepatocellular carcinoma (HCC) in HIV-infected patients has become a serious problem when managing these patients. There are many explanations for this disease evolution, which notably include their longer survival under effective antiviral therapy and also the more rapid evolution of chronic liver disease. Despite recent advances in the management of hepatitis B (HBV) and hepatitis C (HCV) viral diseases, which will probably increase the number of patients achieving a virological response, HIV-infected patients with cirrhosis are still at risk of the onset of HCC. This evolution to HCC is also correlated to other comorbidities such as excessive alcohol consumption and nonalcoholic steatohepatitis (NASH). HCC thus remains a public health issue in this population. The poor prognosis and aggressiveness of HCC have been fully demonstrated, but the mechanisms underlying this aggressiveness are not yet well defined. As well as underlying mechanisms that contribute to accelerating hepatocarcinogenesis in HIV-infected patients, there are other reasons why HIV-infected patients should be considered a higher risk population. This review discusses the principal epidemiological determinants; the mechanisms of pathogenesis; and the treatment of HCC in HIV/HBV and HIV/HCV coinfected patients. It also discusses the probable need to develop a specific screening policy for HCC in this population in order to prevent the rapid development and to make them more amenable to a curative treatment.

Free-fatty-acid-regulating effects of fermented red ginseng are mediated by hormones and by the autonomic nervous system

BackgroundUnderstanding what causes changes in the flux of free fatty acids (FFA) is important to elucidate the etiology of metabolic syndrome. The first aim of this study was to test whether or not hormones and the autonomic nervous system influence blood FFA levels. A secondary aim was to test by means of a multiple group path analysis whether the consumption of fermented red ginseng (FRG; Panax ginseng) would influence those causal relationships. MethodsNinety-three postmenopausal women (age 50–73 yr) were randomly divided into two groups. One group (44 women; age, 58.4 ± 5.9 yr; body mass index, 23.6 ± 2.5 kg/m2) was supplied placebo capsules and the other group (49 women, age 58.4 ± 5.5 yr; body mass index, 22.9 ± 2.4 kg/m2) was supplied FRG capsules. Both prior to and after the study (2 wk), blood samples were collected from the participants and several blood variables were measured and analyzed. ResultsSquared multiple correlations of FFA were 0.699 in the placebo group and 0.707 in the FRG group. The unstandardized estimate of estradiol (E2) for FFA was 0.824 in both groups. ConclusionThe path coefficients of cortisol and the branchial pulse for FFA were significantly different between the FRG group and the placebo group.

Epidemiology and Candidate Genes of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low-grade inflammation in the liver. A large body of clinical and experimental data shows that an increased flux of free fatty acids from increased visceral adipose tissue can lead to NAFLD and insulin resistance. Thus, patients with obesity, insulin resistance, and dyslipidemia are at the greatest risk for NAFLD. Many people believe NAFLD is one of the phenotypes of metabolic syndrome or insulin resistance. In the United States, NAFLD prevalence was reported to be approximately 34% in the adult population. In previous studies performed in Korea, NAFLD prevalence varied from 17.9% to 27.4%, depending on the study populations and diagnostic methods. Prevalence of NAFLD confirmed by liver biopsy was 51.4% in living liver donors in Korea. Recent data showed that NAFLD prevalence was 27.3% (38.3% in men and 12.6% in women) among 161,891 Seoul and Gyeonggi-province residents receiving a health examination from January 2009 to December 2010. Insulin resistance is a major feature and pathogenic factor of NAFLD. Theoretically, genetic variation in candidate genes related to insulin resistance may contribute to the pathogenesis of NAFLD. A recent genetic study using the significance analysis of microarrays method reported that 21 candidate genes, from a pool containing thousands of genes, were involved in NAFLD and insulin resistance. Comprehensive investigation of common genes that are potentially pathogenic in the development of NAFLD is warranted. (J Korean Diabetes 2014;15:71-75)

Definition, Pathogenesis, and Natural Progress of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is emerging as a world-wide health problem and is currently recognized as a hepatic manifestation of metabolic syndrome. It is an umbrella term to describe a wide range of diseases from simple steatosis to non-alcoholic hepatosteatosis (NASH) and NSAH-related liver cirrhosis. NAFLD is mainly associated with insulin resistance which allows increased free fatty acid (FFA) flux to the liver by increasing lipolysis from adipose tissue, triggering macrophage/immune activation, decreasing skeletal muscle glucose uptake, and increasing de novo lipogenesis. Increased FFA pool in the liver, in turn, increases lipotoxic intermediates, such as ceramides, diacylglycerols, and lysophosphatidylcholines, which are responsible for mitochondrial dysfunction and endoplasmic reticulum stress, resulting in inflammation of the liver. When inflammation is severe enough to affect stellate cells, hepatic fibrosis can be induced. (J Korean Diabetes 2014;15:65-70)

Effects of resveratrol in experimental and clinical non-alcoholic fatty liver disease

The prevalence of obesity and related conditions like non-alcoholic fatty liver disease (NAFLD) is increasing worldwide and therapeutic options are limited. Alternative treatment options are therefore intensively sought after. An interesting candidate is the natural polyphenol resveratrol (RSV) that activates adenosinmonophosphate-activated protein kinase (AMPK) and silent information regulation-2 homolog 1 (SIRT1). In addition, RSV has known anti-oxidant and anti-inflammatory effects. Here, we review the current evidence for RSV-mediated effects on NAFLD and address the different aspects of NAFLD and non-alcoholic steatohepatitis (NASH) pathogenesis with respect to free fatty acid (FFA) flux from adipose tissue, hepatic de novo lipogenesis, inadequate FFA β-oxidation and additional intra- and extrahepatic inflammatory and oxidant hits. We review the in vivo evidence from animal studies and clinical trials. The abundance of animal studies reports a decrease in hepatic triglyceride accumulation, liver weight and a general improvement in histological fatty liver changes, along with a reduction in circulating insulin, glucose and lipid levels. Some studies document AMPK or SIRT1 activation, and modulation of relevant markers of hepatic lipogenesis, inflammation and oxidation status. However, AMPK/SIRT1-independent actions are also likely. Clinical trials are scarce and have primarily been performed with a focus on overweight/obese participants without a focus on NAFLD/NASH and histological liver changes. Future clinical studies with appropriate design are needed to clarify the true impact of RSV treatment in NAFLD/NASH patients.

Increased De Novo Lipogenesis Is a Distinct Characteristic of Individuals With Nonalcoholic Fatty Liver Disease

There have been few studies of the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyses to compare de novo lipogenesis and fatty acid flux between subjects with NAFLD and those without, matched for metabolic factors (controls). We studied subjects with metabolic syndrome and/or levels of alanine aminotransferase and aspartate aminotransferase >30 mU/L, using magnetic resonance spectroscopy to identify those with high levels (HighLF, n = 13) or low levels (LowLF, n = 11) of liver fat. Clinical and demographic information was collected from all participants, and insulin sensitivity was measured using the insulin-modified intravenous glucose tolerance test. Stable isotopes were administered and gas chromatography with mass spectrometry was used to analyze free (nonesterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis. Subjects with HighLF (18.4% ± 3.6%) had higher plasma levels of FFAs during the nighttime and higher concentrations of insulin than subjects with LowLF (3.1% ± 2.7%; P = .04 and P < .001, respectively). No differences were observed between groups in adipose flux of FFAs (414 ± 195 μmol/min for HighLF vs 358 ± 105 μmol/min for LowLF; P = .41) or production of very-low-density lipoprotein triacylglycerol from FFAs (4.06 ± 2.57 μmol/min vs 4.34 ± 1.82 μmol/min; P = .77). In contrast, subjects with HighLF had more than 3-fold higher rates of de novo fatty acid synthesis than subjects with LowLF (2.57 ± 1.53 μmol/min vs 0.78 ± 0.42 μmol/min; P = .001). As a percentage of triacylglycerol palmitate, de novo lipogenesis was 2-fold higher in subjects with HighLF (23.2% ± 7.9% vs 10.1% ± 6.7%; P < .001); this level was independently associated with the level of intrahepatic triacylglycerol (r = 0.53; P = .007). By administering isotopes to subjects with NAFLD and control subjects, we confirmed that those with NAFLD have increased synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFAs and did not suppress the contribution from de novo lipogenesis on fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.

Contribution of very low-density lipoprotein triglyceride fatty acids to postabsorptive free fatty acid flux in obese humans

ObjectiveIn the fasting state, plasma free fatty acids (FFA) are thought to derive almost exclusively from adipose tissue lipolysis. However, there are mixed reports as to whether the spillover of fatty acids (FA) from very low-density lipoprotein triglyceride (VLDL–TG) hydrolysis contributes significantly to the plasma FFA pool. Because substantial VLDL–TG fatty acid spillover into the plasma FFA pool would profoundly impact the interpretation of isotope dilution measures of FFA flux, we investigated the contribution of VLDL–TG spillover to plasma FFA appearance. Materials/MethodsEighteen obese adults (15 women) participated in these studies. Each volunteer received a primed, continuous infusion of their own ex-vivo labeled ([1-14C]triolein) VLDL–TG and a continuous infusion of [U-13C]oleate (8nmol·kg fat free mass−1·min−1) to measure VLDL–TG and FFA rate of appearance (Ra), respectively. The presence of 14C-oleate in the plasma FFA–oleate pool was used to calculate the contribution of spillover from VLDL–TG–oleate to the plasma FFA–oleate Ra. ResultsThe spillover rate of VLDL–TG–oleate into plasma FFA–oleate was 6±2μmol/min (7%±2% of [14C]oleate from VLDL–TG) and FFA–oleate flux was 240±61μmol/min. Thus, only 3%±1% of total plasma FFA–oleate appearance could be accounted for by VLDL–TG spillover. ConclusionThe contribution of VLDL–TG spillover to the total plasma FFA pool is negligible and will not materially affect the interpretation of FFA flux measures as an index of adipose tissue lipolysis.

Alcohol and plasma triglycerides

This study reviews recent developments concerning the effects of alcohol on plasma triglycerides. The focus will be on population, intervention and metabolic studies with respect to alcohol and plasma triglycerides. Alcohol consumption and fat ingestion are closely associated and stimulated by each other via hypothalamic signals and by an elevated cephalic response. A J-shaped relationship between alcohol intake and plasma triglycerides has been described. A normal body weight, polyphenols in red wine and specific polymorphisms of the apolipoprotein A-V and apolipoprotein C-III genes may protect against alcohol-associated hypertriglyceridemia. In contrast, obesity exaggerates alcohol-associated hypertriglyceridemia and therefore the risk of pancreatitis. High alcohol intake remains harmful since it is associated with elevated plasma triglycerides, but also with cardiovascular disease, alcoholic fatty liver disease and the development of pancreatitis. Alcohol-induced hypertriglyceridemia is due to increased very-low-density lipoprotein secretion, impaired lipolysis and increased free fatty acid fluxes from adipose tissue to the liver. However, light to moderate alcohol consumption may be associated with decreased plasma triglycerides, probably determined by the type of alcoholic beverage consumed, genetic polymorphisms and lifestyle factors. Nevertheless, patients should be advised to reduce or stop alcohol consumption in case of hypertriglyceridemia.