Hepatic Fat Research Articles

Refined mackerel oil increases hepatic lipid accumulation and reduces choline and choline-containing metabolites in the liver tissue in mice fed a Western diet

In this study, we aimed to evaluate the impact of consuming refined mackerel oil (MO) from rest raw material on hepatic fat accumulation, glucose tolerance, and metabolomic changes in the liver from male C57BL/6N mice. The mice were fed either a Western diet (WD) or a chow diet, with 30 g or 60 g MO per kg of diet (3% or 6%) for 13 weeks. Body weight, energy intake, and feed efficiency were monitored throughout the experiment. A glucose tolerance test was conducted after 11 weeks, and metabolomic analyses of the liver were performed at termination.Inclusion of MO in the WD, but not in the chow diet, led to increased liver weight, hepatic lipid accumulation, elevated fasting blood glucose, reduced glucose tolerance, and insulin sensitivity. Hepatic levels of eicosapentaenoic and docosahexaenoic acid increased, but no changes in levels of saturated and monounsaturated fatty acids were observed. The liver metabolomic profile was different between mice fed a WD with or without MO, with a reduction in choline ether lipids, phosphatidylcholines, and sphingomyelins in mice fed MO.This study demonstrates that supplementing the WD, but not the chow diet, with refined MO accelerates accumulation of hepatic fat droplets and negatively affects blood glucose regulation. The detrimental effects of supplementing a WD with MO were accompanied by increased fat digestibility and overall energy intake, and lower levels of choline and choline-containing metabolites in liver tissue.

E3 ubiquitin ligase Siah1 aggravates NAFLD through Scp2 ubiquitination

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver disorders and accompanied by multiple metabolic dysfunctions. Although excessive lipid accumulation in hepatocytes has been identified as a crucial mediator of NAFLD development, the underlying mechanisms are very complicated and remain largely unknown. In this study, we reported that upregulated expression of the seven in absentia homolog 1 (Siah1) in the liver exacerbated NAFLD progression. Conversely, Siah1 downregulation markedly alleviated the high fat diet-induced accumulation of hepatic fat and expression of genes related to lipid metabolism in vitro and in vivo. The mechanistic study revealed that Siah1 interacted with sterol carrier protein 2 (Scp2) and promotes its ubiquitination and degradation, suggesting that Siah1 is an important activator of Scp2 ubiquitination in the context of NAFLD. Our results demonstrated that Siah1 regulated the lipid accumulation in NAFLD by interacting with Scp2. Thus, this study presents Siah1 as a promising therapeutic target in the development of NAFLD.

Association Between Alcohol Consumption and Ectopic Fat in the Multi-Ethnic Study of Atherosclerosis.

Background The relationship between alcohol consumption and ectopic fat distribution, both known factors for cardiovascular disease, remains understudied. Therefore, we aimed to examine the association between alcohol consumption and ectopic adiposity in adults at risk for cardiovascular disease. Methods and Results In this cross-sectional analysis, we categorized alcohol intake among participants in MESA (Multi-Ethnic Study of Atherosclerosis) as follows (drinks/day): <1 (light drinking), 1 to 2 (moderate drinking), >2 (heavy drinking), former drinking, and lifetime abstention. Binge drinking was defined as consuming ≥5 drinks on 1 occasion in the past month. Visceral, subcutaneous, and intermuscular fat area, pericardial fat volume, and hepatic fat attenuation were measured using noncontrast computed tomography. Using multivariable linear regression, we examined the associations between categories ofalcohol consumption and natural log-transformed fat in ectopic depots. We included 6756 MESA participants (62.1±10.2 years; 47.2% women), of whom 6734 and 1934 had chest computed tomography (pericardial and hepatic fat) and abdominal computed tomography (subcutaneous, intermuscular, and visceral fat), respectively. In adjusted analysis, heavy drinking, relative to lifetime abstention, was associated with a higher (relative percent difference) pericardial 15.1 [95% CI, 7.1-27.7], hepatic 3.4 [95% CI, 0.1-6.8], visceral 2.5 [95% CI, -10.4 to 17.2], and intermuscular 5.2 [95% CI, -6.6 to 18.4] fat but lower subcutaneous fat -3.5 [95% CI, -15.5 to 10.2]). The associations between alcohol consumption and ectopic adiposity exhibited a J-shaped pattern. Binge drinking, relative to light-to-moderate drinking, was also associated with higher ectopic fat. Conclusions Alcohol consumption had a J-shaped association with ectopic adiposity. Both heavy alcohol intake and binge alcohol drinking were associated with higher ectopic fat.

Transient hepatic attenuation difference (THAD) or fat sparing? Aberrant right gastric vein (ARGV) determining a pseudolesion at the border of the IInd/IIIrd liver segments. Review of developmental concepts.

The aberrant right gastric vein (ARGV) is a rare anatomical variation. It can be responsible for unexplained hyperdensities in the hepatic parenchyma on CT scans, also known as third inflow effects. We present two cases sharing similar vascular pattern and slightly different imagistic findings on ultrasound and computer-tomography performed studies. Both ultrasonographies showed a nodular-geographic hypoechoic area within a hyperechogenic fatty liver. Further CT evaluation showed in both cases a hyperattenuating homogenous area clearly visible on all four phases at the border of the IInd/IIIrd hepatic segment, that enhance especially on the portal venous phase, with no slow-fill, wash-out, central scar or rim-like features. The areas were considered to be focal fat sparing areas in diffuse fatty liver or a perfusion disorder due to the presence of an aberrant right gastric vein. The aim of this paper is to discuss the embryological aspects which are the groundwork for this vascular anomaly and to correlate the findings with imagistic aspects. These two ARGV produced pseudolesions, understood as focal fat sparing areas within diffuse fatty livers. These pseudolesions mimic liver tumours, therefore it is important to look for such an aberrant vessel in order to rule out other diagnoses.

Hepatic MR imaging using IDEAL-IQ sequence: Will Gd-EOB-DTPA interfere with reproductivity of fat fraction quantification?

Iterative decomposition of water and fat with echo asymmetry and least squares estimation quantification sequence (IDEAL-IQ) is based on chemical shift-based water and fat separation technique to get proton density fat fraction. Multiple studies have shown that using IDEAL-IQ to test the stability and repeatability of liver fat is acceptable and has high accuracy. To explore whether Gadoxetate Disodium (Gd-EOB-DTPA) interferes with the measurement of the hepatic fat content quantified with the IDEAL-IQ and to evaluate the robustness of this technique. IDEAL-IQ was used to quantify the liver fat content at 3.0T in 65 patients injected with Gd-EOB-DTPA contrast. After injection, IDEAL-IQ was estimated four times, and the fat fraction (FF) and R2* were measured at the following time points: Pre-contrast, between the portal phase (70 s) and the late phase (180 s), the delayed phase (5 min) and the hepatobiliary phase (20 min). One-way repeated-measures analysis was conducted to evaluate the difference in the FFs between the four time points. Bland-Altman plots were adopted to assess the FF changes before and after injection of the contrast agent. P < 0.05 was considered statistically significant. The assessment of the FF at the four time points in the liver, spleen and spine showed no significant differences, and the measurements of hepatic FF yielded good consistency between T1 and T2 [95% confidence interval: -0.6768%, 0.6658%], T1 and T3 (-0.3900%, 0.3178%), and T1 and T4 (-0.3750%, 0.2825%). R2* of the liver, spleen and spine increased significantly after injection (P < 0.0001). Using the IDEAL-IQ sequence to measure the FF, we can obtain results that will not be affected by Gd-EOB-DTPA. The high reproducibility of the IDEAL-IQ sequence makes it available in the scanning interval to save time during multiphase examinations.

Ectopic lipid deposition in muscle and liver, quantified by proton magnetic resonance spectroscopy.

Advances in the development of noninvasive imaging techniques have spurred investigations into ectopic lipid deposition in the liver and muscle and its implications in the development of metabolic diseases such as type 2 diabetes. Computed tomography and ultrasound have been applied in the past, though magnetic resonance-based methods are currently considered the gold standard as they allow more accurate quantitative detection of ectopic lipid stores. This reviewfocuses on methodological considerations of magnetic resonance-based methods to image hepatic and muscle fat fractions, and it emphasizes anatomical and morphological aspects and how these may influence data acquisition, analysis, and interpretation.

Increased risk of cardiometabolic disease in normal-weight individuals with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with obesity, but there is increasing evidence that not all individuals who are overweight/obese also develop NAFLD. Currently, it is unclear whether normal-weight (Nw) individuals with NAFLD have a higher risk of cardiometabolic disease risk compared with individual sub-groups (Nw and Obesity [Ob]) of non-NAFLD. This study aimed to compare the cardiometabolic profiles, cardiovascular disease, and diabetes between Nw vs. Ob with non-NAFLD vs. NAFLD. This study utilized the Korea National Health and Nutrition Examination Surveys collected from 2019 to 2021. Individuals were stratified into Nw vs. Ob categories and further divided into non-NAFLD and NAFLD groups based on the hepatic steatosis index and liver fat score (N=6615). The prevalence of non-NAFLD Nw, non-NAFLD Ob, NAFLD Nw, and NAFLD Ob groups was 36%, 20%, 7%, and 37%, respectively. NAFLD Nw vs. non-NAFLD Ob manifests deteriorated cardiometabolic disease risk profiles and surrogate markers of insulin resistance despite having higher weight, waist circumference, and BMI. In addition, compared to non-NAFLD Nw, individuals with NAFLD Nw had a significantly higher risk of CVDs (738%, p<.001) and diabetes (408%, p<.001), with no difference between NAFLD Nw and NAFLD Ob groups. Cardiometabolic disease risk is more closely related to NAFLD developments than adiposity status. Therefore, not all overweight/obese individuals have a higher cardiometabolic disease risk, and NAFLD in Nw is an aggressive disease that is associated with cardiometabolic disease risk compared with Ob individuals without NAFLD.

Blood-derived lysophospholipid sustains hepatic phospholipids and fat storage necessary for hepatoprotection in overnutrition.

The liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (Mfsd2a) as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust nonalcoholic steatohepatitis-like (NASH-like) phenotype within just 2 weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFAs). Treating hepatocytes with LPCs containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid docosahexaenoic acid (DHA) promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA-containing LPCs drive hepatic lipid droplet formation, suppress lipogenesis, and sustain hepatic phospholipid pools - processes that are critical for protecting the liver from excess dietary fat.

The role of long non-coding RNAs in carbohydrate and fat metabolism in the liver.

The metabolism of carbohydrates and lipids (fat) in the liver is closely interconnected both in physiological conditions and in pathology. This relationship in the body is possible due to the regulation by many factors, including epigenetic ones. Histone modifications, DNA methylation, and non-coding RNAs are considered to be the main epigenetic factors. Non-coding RNAs (ncRNAs) refers to ribonucleic acid (RNA) molecules that do not code for a protein. They cover a huge number of RNA classes and perform a wide range of biological functions such as regulating gene expression, protecting the genome from exogenous DNA, and directing DNA synthesis. One such class of ncRNAs that has been extensively studied are long non-coding RNAs (lncRNAs). The important role of lncRNAs in the formation and maintenance of normal homeostasis of biological systems, as well as participation in many pathological processes, has been proven. The results of recent studies indicate the importance of lncRNAs in lipid and carbohydrate metabolism. Modifications of lncRNAs expression can lead to disruption of biological processes in tissues, including fat and protein, such as adipocyte proliferation and differentiation, inflammation, and insulin resistance. Further study of lncRNAs made it possible to partly determine the regulatory mechanisms underlying the formation of an imbalance in carbohydrate and fat metabolism individually and in their relationship, and the degree of interaction between different types of cells involved in this process. This review will focus on the function of lncRNAs and its relation to hepatic carbohydrate and fat metabolism and related diseases in order to elucidate the underlying mechanisms and prospects for studies with lncRNAs.

Aetiology of Type 2 diabetes in people with a 'normal' body mass index: testing the personal fat threshold hypothesis.

Weight loss in overweight or obese individuals with Type 2 diabetes (T2D) can normalize hepatic fat metabolism, decrease fatty acid oversupply to β cells and restore normoglycaemia. One in six people has BMI <27 kg/m2 at diagnosis, and their T2D is assumed to have different aetiology. The Personal Fat Threshold hypothesis postulated differing individual thresholds for lipid overspill and adverse effects on β-cell function. To test this hypothesis, people with Type 2 diabetes and body mass index <27kg/m2 (n = 20) underwent repeated 5% weight loss cycles. Metabolic assessments were carried out at stable weight after each cycle and after 12 months. To determine how closely metabolic features returned to normal, 20 matched normoglycemic controls were studied once. Between baseline and 12 months: BMI fell (mean ± SD), 24.8 ± 0.4 to 22.5 ± 0.4 kg/m2 (P<0.0001) (controls: 21.5 ± 0.5); total body fat, 32.1 ± 1.5 to 27.6 ± 1.8% (P<0.0001) (24.6 ± 1.5). Liver fat content and fat export fell to normal as did fasting plasma insulin. Post-meal insulin secretion increased but remained subnormal. Sustained diabetes remission (HbA1c < 48 mmol/mol off all glucose-lowering agents) was achieved by 70% (14/20) by initial weight loss of 6.5 (5.5-10.2)%. Correction of concealed excess intra-hepatic fat reduced hepatic fat export, with recovery of β-cell function, glycaemic improvement in all and return to a non-diabetic metabolic state in the majority of this group with BMI <27 kg/m2 as previously demonstrated for overweight or obese groups. The data confirm the Personal Fat Threshold hypothesis: aetiology of Type 2 diabetes does not depend on BMI. This pathophysiological insight has major implications for management.

Unravelling Effects of Rosemary (Rosmarinus officinalis L.) Extract on Hepatic Fat Accumulation and Plasma Lipid Profile in Rats Fed a High-Fat Western-Style Diet.

The objective of the study was to investigate the preventive effect on obesity-related conditions of rosemary (Rosmarinus officinalis L.) extract (RE) in young, healthy rats fed a high-fat Western-style diet to complement the existing knowledge gap concerning the anti-obesity effects of RE in vivo. Sprague Dawley rats (71.3 ± 0.46 g) were fed a high-fat Western-style diet (WD) or WD containing either 1 g/kg feed or 4 g/kg feed RE for six weeks. A group fed standard chow served as a negative control. The treatments did not affect body weight; however, the liver fat percentage was reduced in rats fed RE, and NMR analyses of liver tissue indicated that total cholesterol and triglycerides in the liver were reduced. In plasma, HDL cholesterol was increased while triglycerides were decreased. Rats fed high RE had significantly increased fasting plasma concentrations of Glucagon-like peptide-1 (GLP-1). Proteomics analyses of liver tissue showed that RE increased enzymes involved in fatty acid oxidation, possibly associated with the higher fasting GLP-1 levels, which may explain the improvement of the overall lipid profile and hepatic fat accumulation. Furthermore, high levels of succinic acid in the cecal content of RE-treated animals suggested a modulation of the microbiota composition. In conclusion, our results suggest that RE may alleviate the effects of consuming a high-fat diet through increased GLP-1 secretion and changes in microbiota composition.

Research Note: Effect of increasing fat supplementation in diets on productive performance, egg quality, and fatty liver incidence in laying hens throughout the entire laying cycle

This study aimed to investigate the effect of increasing fat supplementation in diets on productive performance, egg quality, and fatty liver incidence in laying hens during the entire laying cycle. A total of three hundred eighty-four 18-wk-old Hy-Line Brown laying hens were randomly allotted to 1 of 3 dietary treatments with 8 replicates for a 52-wk feeding trial. Each replicate comprised 16 consecutive cages with 1 hen per cage. The experimental diets were prepared by supplementing 0, 1.5, or 3.0% tallow to a basal diet, but all nutrients and energy in 3 diets were formulated to be equalized according to the recommended nutrient and energy concentrations at each phase of laying hens. Results indicated that increasing fat supplementation in diets decreased (linear, P < 0.01) feed conversion ratio (FCR) by increased egg mass (linear, P < 0.05) but decreased feed intake (linear and quadratic, P < 0.05) in laying hens during overall periods. Increasing fat supplementation in diets decreased (linear and quadratic, P < 0.05) egg yolk color during overall periods. Increasing fat supplementation in diets had no effects on liver color and hemorrhagic score measured at 60 wk (phase 3) and 70 wk of age (phase 4) without affecting hepatic fat concentrations during overall periods. However, the relative abdominal fat weight in laying hens was increased (linear and quadratic, P < 0.05) during overall periods by increasing fat supplementation in diets. In conclusion, increasing fat supplementation up to 3.0% in diets improves FCR with no impacts on fatty liver incidence and economics in laying hens throughout the entire laying cycle.

The effects of GLP-1 receptor agonists on visceral fat and liver ectopic fat in an adult population with or without diabetes and nonalcoholic fatty liver disease: A systematic review and meta-analysis.

To uncover the effect of GLP-1 receptor agonists (GLP-1 RAs) on the visceral- and hepatic fat content of adults. PubMed, EMBASE, Cochrane Library, and Web of Science were searched from inception until November 2022. Randomized controlled trials (RCTs) of GLP-1Ras was extracted, including reports of effects on visceral adipose tissue and hepatic fat content in individuals with type 2 diabetes, non-type 2 diabetes, NAFLD (non-alcoholic fatty liver disease), and non-NAFLD. Meta-analyses used random-effects models. 1736 individuals in the 30 qualified RCTs were included, comprising 1363 people with type 2 diabetes and 318 with NFLD. GLP-1 RAs reduced visceral adipose tissue (standard mean difference [SMD] = -0.59, 95% CI [-0.83, -0.36], P<0.00001) and hepatic fat content (weighted mean difference [WMD] = -3.09, 95% CI [-4.16, -2.02], P<0.00001) compared to other control treatment. Subgroup analysis showed that GLP-1Ras dramatically decreased visceral fat in patients with type 2 diabetes (SMD = -0.49, 95% CI [-0.69, -0.29] P<0.00001), NAFLD (SMD = -0.99, 95% CI [-1.64, -0.34] P = 0.003), non-type 2 diabetes (SMD = -1.38, 95% CI [-2.44, -0.32] P = 0.01), and non-NAFLD (SMD = -0.53, 95% CI [-0.78, -0.28] P<0.0001). GLP-1Ras reduced the liver fat level of type 2 diabetes (WMD = -3.15, 95% CI [-4.14, -2.15] P<0.00001), NAFLD (WMD = -3.83, 95% CI [-6.30, -1.37] P = 0.002), and type 2 diabetes with NAFLD (WMD = -4.27, 95% CI [-6.80, -1.74] P = 0.0009), while showed no impact on the hepatic fat content in non-Type 2 diabetes (WMD = -12.48, 95% CI [-45.19, 20.24] P = 0.45). LP-1 RAs significantly reduce visceral- and liver fat content in adults.

Non-Alcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma: Effect of Hepatic Steatosis on Major Hepatocellular Carcinoma Features at MRI

Background Non-alcoholic fatty liver disease has become the leading chronic liver disease in the developed world, with a prevalence of 6%-35%. Its pathological spectrum ranges from simple steatosis (non-alcoholic fatty liver) to different degrees of inflammation and liver cell damage [nonalcoholic steatohepatitis (NAFLD)]. NAFLD has gained attention in recent years because of its association with hepatocellular carcinoma (HCC). Objective To see how hepatic fat fraction affects LIRADS major hepatocellular carcinoma features on magnetic resonance imaging. Patients and Methods Our study included 60 patients who had had a liver MR scan and exhibited MRI features in keeping with HCC. We categorize the patients into two groups: hepatic steatosis and non- hepatic steatosis groups based on MRI hepatic fat signal fraction. LI-RADS major and ancillary features were evaluated in all HCCs. Between October 2021 and April 2022, a retrospective search was conducted to find all patients with HCC who underwent an MRI of the liver at the radiology department of Ain Shams University's Faculty of medicine. Results In the current study, a higher proportion of HCCs show non- enhancing capsule in patients with hepatic steatosis; 5 HCC (5/30; 16.7%), while in the non-hepatic steatosis group no HCCs 0 (0%) showed non-enhancing capsule. The effect of ancillary features on diagnostic accuracy is still being researched. As regards the impact of the degree of fatty liver on the major and ancillary HCC features, the “enhancing capsule”, “mild-moderate T2 hyperintensity” and “restricted DWI” features are less commonly seen in cases of moderate to severe hepatic steatosis than in those of mild hepatic steatosis. Our study also showed that HCCs tends to be of a smaller size as the hepatic steatosis degree increased. Conclusion The findings of our retreopective study are coincide with a recent retrospective studies demonstrated that “enhancing capsule” feature of HCC was less frequently observed in patients with hepatic steatosis compared to non-hepatic steatosis patients. We compared the MRI features of HCC in patients with hepatic steatosis to those in patients without hepatic steatosis. Our findings imply that existing imaging criteria for the noninvasive characterization of HCC in individuals with hepatic steatosis should be utilised with care.

MRI Spectroscopy as a Diagnostic Model for Assessment of Liver Steatosis in NAFLD Non-Diabetic Patients

Abstract Background Non-alcoholic fatty liver disease, the hepatic pandemic of the XXI century, being the number one cause of chronic hepatic disease in the occidental world. Aim of the Work To evaluate the diagnostic performance of MRI spectroscopy for assessing hepatic steatosis in nonalcoholic fatty liver disease (NAFLD) in non diabetic patients. Patients and Methods A case control study was conducted on 40 patients inhepatology and gastroenterology department &amp; Radiology department ain shams university hospital from Jan 2020 to November 2020 to study role of MRI spectroscopy as adiagnostic model for assessment of liver steatosis in NAFLD non diabetic patients. Results There was statically significant Positive correlation Between hepatic steatosis score, fat peak and fat fraction %, and there was statically significant Negative correlation Between Hepatic steatosis score and water peak. Conclusion MRI Spectroscopy can be reliably used as an accurate and specific noninvasive method for the diagnosis of Nonalcoholic fatty Liver Disease.

Elevated Plasma Copeptin Levels Identify the Presence and Severity of Nonalcoholic Fatty Liver Disease in Obesity

Abstract Background Non-alcoholic fatty liver disease is characterized by excessive fat accumulation in the liver with unclear mechanism may be due to epigenetic changes which take place at the transcriptional level without altering the underlying DNA sequence. this epigenetic alternation are involved in regulation of hepatic lipid metabolism, insulin resistance, mitochondrial damage, oxidative stress response, and the release of inflammatory cytokines, all of which have been implicated in the development and progression of NAFLD. Elevated copeptin, a vasopressin marker, is linked to metabolic disease, and obese rats with lowvasopressin concentration had a decreased risk of liver steatosis. Aim and objectives To Detect the elevation of plasma copeptin in obese patients with nonalcoholic fatty liver disease in relation to general population. Subjects and Methods This is A randomized case control cross sectional study, was carried out at internal medicine and gastroenterology department, Ain Shams University hospitals, on 100 patients above 18 years old with Hepatic Steatosis Index (HSI) and NAFLD-Liver Fat Score (LFS), over a period of 6 months. Result There was high statistically significant difference between the studied groups as regard Serum plasma copeptin. Conclusion Our study demonstrates for the first time that copeptin levels predict the presence of biopsy-proven NAFLD in obese individuals, regardless of body adiposity and the coexistence of other metabolic disorders. Studies with longitudinal design are warranted for exploring the possible involvement of AVP/V1aR system in the development and progression of NAFLD.

Reduction of lauric acid content in virgin coconut oil improved plasma lipid profile in high-fat diet-induced hypercholesterolemic mice.

Virgin coconut oil (VCO) is claimed to have various health benefits, but favorable effects of its major component (∼50%), lauric acid, are controversial. Therefore, we aimed to reduce lauric acid content (∼30%) in VCO and evaluate its effect compared to VCO and medium-chain triglycerides (MCT), on food intake, bodyweight (BW), lipid profiles, and hepatic histology. Female C57BL/6 mice were treated with different diets for 3 months: control (normal diet), high-fat diet (HF), HF+VCO, HF+MCT, HF+low lauric acid VCO (LLA), and normal diet+LLA (C+LLA). LLA was prepared by enzymatic interesterification of VCO with methyl octanoate (methyl caprylate) and methyl decanoate (methyl caprate). Plasma and liver lipids, including total cholesterol (TC), high-density lipoprotein (HDL), and triglyceride, were measured by colorimetric assay, and hepatic fat accumulation was examined by oil-red-O staining. HF mice exhibited high plasma and liver TC and low-density lipoprotein (LDL). VCO or MCT treatment lowered liver TC and LDL, whereas LLA increased plasma HDL and markedly improved TC:HDL ratio. The HF-induced hepatic fat accumulation was attenuated by all treatments, of which VCO was the most effective. Control mice administered with LLA demonstrated lower liver TC and LDL, but higher plasma TC and HDL compared to controls. Lowest BW gain and food intake were found in mice treated with LLA. In conclusion, VCO, MCT, and LLA ameliorated hepatic histopathology caused by HF. VCO and MCT improved liver lipid profiles, whereas LLA has more beneficial effect on plasma lipids via a better TC:HDL ratio and showed promise for BW control.

Hepatocyte Aquaporins AQP8 and AQP9 Are Engaged in the Hepatic Lipid and Glucose Metabolism Modulating the Inflammatory and Redox State in Milk-Supplemented Rats.

Milk is an important source of nutrients and energy, but there are still many uncertainties regarding the health effects of milk and dairy products consumption. Milk from different species varies in physicochemical and nutritional properties. We previously showed that dietary supplements with different milks in rats trigger significant differences in metabolic and inflammatory states, modulating mitochondrial functions in metabolically active organs such as the liver and skeletal muscle. Here, we have deepened the effects of isoenergetic supplementation of milk (82 kJ) from cow (CM), donkey (DM) or human (HM) on hepatic metabolism to understand the interlink between mitochondrial metabolic flexibility, lipid storage and redox state and to highlight the possible role of two hepatocyte aquaporins (AQPs) of metabolic relevance, AQP8 and AQP9, in this crosstalk. Compared with rats with no milk supplementation, DM- and HM-fed rats had reduced hepatic lipid content with enhanced mitochondrial function and decreased oxidative stress. A marked reduction in AQP8, a hydrogen peroxide channel, was seen in the liver mitochondria of DM-fed rats compared with HM-fed, CM-fed and control animals. DM-fed or HM-fed rats also showed reduced hepatic inflammatory markers and less collagen and Kupffer cells. CM-fed rats showed higher hepatic fat content and increased AQP9 and glycerol permeability. A role of liver AQP8 and AQP9 is suggested in the different metabolic profiles resulting from milk supplementation.

Bioactive oxylipins in type 2 diabetes mellitus patients with and without hypertriglyceridemia.

Dyslipidemia, in particular elevated triglycerides (TGs) contribute to increased cardiovascular risk in type 2 diabetes mellitus (T2DM). In this pilot study we aimed to assess how increased TGs affect hepatic fat as well as polyunsaturated fatty acid (PUFA) metabolism and oxylipin formation in T2DM patients. 40 patients with T2DM were characterized analyzing routine lipid blood parameters, as well as medical history and clinical characteristics. Patients were divided into a hypertriglyceridemia (HTG) group (TG ≥ 1.7mmol/l) and a normal TG group with TGs within the reference range (TG < 1.7mmol/l). Profiles of PUFAs and their oxylipins in plasma were measured by gas chromatography and liquid chromatography/tandem mass spectrometry. Transient elastography (TE) was used to assess hepatic fat content measured as controlled attenuation parameter (CAP) (in dB/m) and the degree of liver fibrosis measured as stiffness (in kPa). Mean value of hepatic fat content measured as CAP as well as body mass index (BMI) were significantly higher in patients with high TGs as compared to those with normal TGs, and correlation analysis showed higher concentrations of TGs with increasing CAP and BMI scores in patients with T2DM. There were profound differences in plasma oxylipin levels between these two groups. Cytochrome P450 (CYP) and lipoxygenase (LOX) metabolites were generally more abundant in the HTG group, especially those derived from arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), γ-linolenic acid (γ-LA), and α-linolenic acid (α-LA), and a strong correlation between TG levels and plasma metabolites from different pathways was observed. In adult patients with T2DM, elevated TGs were associated with increased liver fat and BMI. Furthermore, these patients also had significantly higher plasma levels of CYP- and LOX- oxylipins, which could be a novel indicator of increased inflammatory pathway activity, as well as a novel target to dampen this activity.

P21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1

PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. However, its regulatory mechanism is largely unknown. Here, we report that oncoprotein p21-activated kinase 4 (PAK4) is an NCoR1 kinase. Specifically, PAK4 phosphorylates NCoR1 at T1619/T2124, resulting in an increase in its nuclear localization and interaction with PPARα, thereby repressing the transcriptional activity of PPARα. We observe impaired ketogenesis and increases in PAK4 protein and NCoR1 phosphorylation levels in liver tissues of high fat diet-fed mice, NAFLD patients, and hepatocellular carcinoma patients. Forced overexpression of PAK4 in mice represses ketogenesis and thereby increases hepatic fat accumulation, whereas genetic ablation or pharmacological inhibition of PAK4 exhibites an opposite phenotype. Interestingly, PAK4 protein levels are significantly suppressed by fasting, largely through either cAMP/PKA- or Sirt1-mediated ubiquitination and proteasome degradation. In this way, our findings provide evidence for a PAK4-NCoR1/PPARα signaling pathway that regulates fatty acid β-oxidation and ketogenesis.