Dietary Betaine Mitigates Hepatic Steatosis and Inflammation Induced by a High-Fat-Diet by Modulating the Sirt1/Srebp-1/Pparɑ Pathway in Juvenile Black Seabream (Acanthopagrus schlegelii).

The present study aimed to elucidate the mechanism of dietary betaine, as a lipid-lowering substance, on the regulation of lipid metabolism and inflammation in juvenile black seabream (Acanthopagrus schlegelii) fed a high fat diet. An 8-week feeding trial was conducted in black seabream with an initial weight of 8.39 ± 0.01g fed four isonitrogenous diets including Control, medium-fat diet (11%); HFD, high-fat diet (17%); and HFD supplemented with two levels (10 and 20 g/kg) of betaine, HFD+B1 and HFD+B2, respectively. SGR and FE in fish fed HFD+B2 were significantly higher than in fish fed HFD. Liver histology revealed that vacuolar fat droplets were smaller and fewer in bream fed HFD supplemented with betaine compared to fish fed HFD. Betaine promoted the mRNA and protein expression levels of silent information regulator 1 (Sirt1), up-regulated mRNA expression and protein content of lipid peroxisome proliferator-activated receptor alpha (pparα), and down-regulated mRNA expression and protein content of sterol regulatory element-binding protein-1(srebp-1). Furthermore, the mRNA expression levels of anti-inflammatory cytokines in liver and intestine were up-regulated, while nuclear factor kB (nf-kb) and pro-inflammatory cytokines were down-regulated by dietary betaine supplementation. Likewise, in fish that received lipopolysaccharide (LPS) to stimulate inflammatory responses, the expression levels of mRNAs of anti-inflammatory cytokines in liver, intestine and kidney were up-regulated in fish fed HFD supplemented with betaine compared with fish fed HFD, while nf-kb and pro-inflammatory cytokines were down-regulated. This is the first report to suggest that dietary betaine could be an effective feed additive to alleviate hepatic steatosis and attenuate inflammatory responses in black seabream fed a high fat diet by modulating the Sirt1/Srebp-1/Pparɑ pathway.

IRE1α-JNK pathway-mediated autophagy promotes cell survival in response to endoplasmic reticulum stress during the initial phase of hepatic steatosis.

AIMS: It has been widely reported that autophagy and inositol-requiring enzyme-1α (IRE1α)-c-Jun N-terminal kinase (JNK) pathway was involved in cell survival under endoplasmic reticulum (ER) stress, but their specific roles in hepatic steatosis remain unclear. This study aimed to determine the interaction between autophagy and IRE1α-JNK pathway on cell survival in response to ER stress during the initial phase of hepatic steatosis. METHODS: Hepatic steatosis was induced in HepG2 cells by supplementing oleic acid (OA). Lipid accumulation was evaluated by BODIPY493/503 staining. ER stress and IRE1α-JNK signaling were investigated by western blot. Autophagy was monitored by western blot, GFP-LC3 plasmid and immunofluorescence staining, while apoptosis was determined by western blotting, Annexin-V-FITC/PI staining and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. KEY FINDINGS: Aggravated lipid accumulation was found under increased ER stress during the initial phase of hepatic steatosis. Meanwhile, an increase of autophagy and no alteration of apoptosis were observed under increased ER stress. Interestingly, autophagy was induced by ER stress, while autophagy suppression led to an increase of apoptosis in response to ER stress Moreover, further study showed that IRE1α-JNK pathway was activated after ER stress and consequently induced autophagy, which promoted cell survival in the initial phase of hepatic steatosis. SIGNIFICANCE: We conclude that IRE1α-JNK pathway was activated during ER stress in the initial phase of hepatic steatosis and promoted cell survival by enhancing autophagy. Targeting IRE1α-JNK-autophagy signaling may provide new insight into preventive strategies for hepatic steatosis.

Zingiber officinale extract administration diminishes steroyl-CoA desaturase gene expression and activity in hyperlipidemic hamster liver by reducing the oxidative and endoplasmic reticulum stress.

BACKGROUND: Stearoyl CoA desaturases (SCD) are enzymes that convert saturated to monounsaturated fatty acids and have increased activity in hepatic steatosis. PURPOSE: We aimed to investigate the potential of ginger extract (GIN) to modulate the liver SCD1 expression and activity in hyperlipidemic (HL) conditions, in order to lower lipid accumulation in the steatotic liver. STUDY DESIGN/METHODS: Male Golden Syrian hamsters were divided in three groups: (i) fed with standard chow (N), (ii) fed with standard chow plus 3% cholesterol and 15% butter for 21 weeks (HL), (iii) HL treated with GIN (800 µg/kg body weight/day) in the last 5 weeks of fat diet (HL-GIN). Cholesterol (C), triglycerides (TG), non-esterified fatty acids (NEFA), SCD1 estimated activity (C16:1n7/C16:0; C18:1n9/C18:0) and gene expression, acetyl-CoA carboxylase (ACC), thiobarbituric acid reactive substances (TBARS), paraoxonase1 (PON1) and myeloperoxidase (MPO) were determined in the plasma and liver of all hamsters. We measured protein expression of endoplasmic reticulum stress (ERS) markers, gene and protein expression of liver X receptor α/ß (LXRα/ß), peroxisome proliferator-activated receptor γ (PPARγ), ATP-binding cassette sub-family G member 5/8 (ABCG5/G8) and 7α-hydroxylase1 (CYP7A1) in all hamsters' livers. RESULTS: In plasma, in HL-GIN versus HL hamsters, SCD1 estimated activity was lower (27%; 15%, p < 0.05), NEFA levels decreased by 91%, p < 0.001, while C and TG levels did not vary; the oxidative stress expressed as MPO and TBARS levels decreased (15%; 11%, p < 0.01), while PON1 protein increased (75%, p < 0.05). In the liver of HL-GIN versus HL, C, TG, NEFA, MPO and TBARS levels decreased (8-40%, p < 0.05) and PON1 protein levels increased (30%, p < 0.05), SCD1 estimated activity decreased (8%; 9%, p < 0.05), in parallel with the reduced gene expression of SCD1 and ACC (70-80%, p < 0.05). The protein expression of the ERS sensors decreased (30-65%, p < 0.05), while that of ABCG5/G8, CYP7A1, LXRα/ß and PPARγ increased in HL-GIN (20-30%, p < 0.05) versus HL liver. CONCLUSION: GIN reduces SCD1 estimated activity and expression, as well as the lipids accumulated in the livers of HL hamsters. This is achieved through a mechanism involving the decrease of the oxidative and ERS, and the enhancement of cholesterol efflux.

Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis.

Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis, has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.

Overexpression of NRK1 ameliorates diet- and age-induced hepatic steatosis and insulin resistance.

NAD+ is a co-enzyme in redox reactions and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Dietary supplementation of NAD+ precursors nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) protects against metabolic disease, neurodegenerative disorders and age-related physiological decline in mammals. Here we sought to identify the roles of nicotinamide riboside kinase 1 (NRK1) plays in regulating hepatic NAD+ biosynthesis and lipid metabolism. Using adenovirus mediated gene transduction to overexpress or knockdown NRK1 in mouse liver, we have demonstrated that NRK1 is critical for maintaining hepatic NAD+ levels and triglyceride content. We have further shown that the hepatic expression of Nmrk1 mRNA is significantly decreased either in mice treated with high-fat diet or in aged mice. However, adenoviral delivery of NRK1 in these diet- and age-induced mice elevates hepatic NAD+ levels, reduces hepatic steatosis, and improves glucose tolerance and insulin sensitivity. Our results provide important insights in targeting NRK1 for treating hepatic steatosis.

Ethanol Extract of Capsella bursa-pastoris Improves Hepatic Steatosis Through Inhibition of Histone Acetyltransferase Activity.

Histone lysine acetylation is thought to play a role in regulating the balance between energy storage and energy expenditure. However, the epigenetic mechanisms by which food phytochemicals influence metabolic processes in the liver have not been thoroughly investigated. In this study, we investigated the effect of an ethanol extract of Capsella bursa-pastoris (ECB) on histone acetyltransferase (HAT) inhibition, and whether it could thereby attenuate lipid accumulation in vitro and in vivo. We observed that ECB inhibits HAT activity as assessed by colorimetric and autoradiography assay systems. ECB also reduced oleic acid (OA)-stimulated histone acetylation at H4K5 and H4K12 and attenuated OA-mediated lipid accumulation in HepG2 cells, in the absence of observable cytotoxicity. We then investigated these effects in vivo. Mice were fed on either a normal diet (ND) or high-fat diet (HFD) in the presence or absence of ECB supplementation. In comparison with the ND controls, the HFD mice exhibited higher body weight, liver fat, adipose tissue size, and total serum cholesterol concentrations, and these effects were significantly attenuated by ECB supplementation. Taken together, these results suggest that ECB protects against the mechanisms responsible for HFD-induced hepatic steatosis, and may involve the targeting of histone H4K acetylation.

Molecular MR Imaging of Myeloperoxidase Distinguishes Steatosis from Steatohepatitis in Nonalcoholic Fatty Liver Disease.

Purpose To test whether MPO-Gd, an activatable molecular magnetic resonance (MR) imaging agent specific for myeloperoxidase (MPO) activity, could detect MPO activity in nonalcoholic steatohepatitis (NASH) mouse models and human liver biopsy samples. Materials and Methods In this study, 20 leptin receptor-deficient and three MPO knockout mice were injected with endotoxin (lipopolysaccharide) or fed a methionine and choline-deficient (MCD) diet to induce experimental NASH and underwent MR imaging with MPO-Gd. Saline-injected and control diet-fed leptin receptor-deficient mice were used as respective controls. MPO protein and activity measurements and histologic analyses were performed. Eleven human liver biopsy samples underwent MPO-Gd-enhanced MR imaging ex vivo and subsequent histologic evaluation. Results were compared with Student t test or Mann-Whitney U test. Results With endotoxin, a significantly increased contrast-to-noise ratio (CNR) was found compared with sham (mean CNR, 1.81 [95% confidence interval {CI}: 1.53, 2.10] vs 1.02 [95% CI: 0.89, 1.14]; P = .03) at MPO-Gd MR imaging. In the diet-induced NASH model, an increased CNR was also found compared with sham mice (mean CNR, 1.33 [95% CI: 1.27, 1.40] vs 0.98 [95% CI: 0.83, 1.12]; P = .008). Conversely, CNR remained at baseline in NASH mice imaged with gadopentetate dimeglumine and in MPO knockout NASH mice with MPO-Gd, which proves specificity of MPO-Gd. Ex vivo molecular MR imaging of liver biopsy samples from NASH and control patients confirmed results from animal studies (mean CNR for NASH vs control patients, 2.61 [95% CI: 1.48, 3.74] vs 1.29 [95% CI: 1.06, 1.52]; P = .004). Conclusion MPO-Gd showed elevated MPO activity in NAFLD mouse models and human liver biopsy samples. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on April 6, 2017.

Lipid Emulsion Added to a Liquid High-Carbohydrate Diet and Voluntary Running Exercise Reduce Lipogenesis and Ameliorate Early-Stage Hepatic Steatosis in Mice.

Background: The use of parenteral nutrition formulas is often associated with the development of hepatic steatosis. We have shown previously that the addition of a lipid emulsion (LE) rich in n-6 (ω-6) fatty acids (FAs) ameliorated triglyceride (TG) accumulation in the livers of nonobese mice fed a high-carbohydrate diet (HCD) for 5 wk. However, it remains unclear how rapidly this condition develops and whether it can be prevented by LE with or without a running wheel for voluntary exercise (Exe).Objective: We investigated in an 8-d study whether mice develop steatosis and whether the administration of LE with or without Exe reduces the concentration of total FAs and prevents an increase in the expression of genes in the liver associated with lipogenesis.Methods: Male C57BL/6 mice aged 5 wk were randomized into 5 groups: standard feed pellet (SFP); a liquid HCD (77% of total energy from carbohydrates and 0.5% from fat); HCD + Exe; HCD + 13.5% LE (67% carbohydrates and 13.5% fat); or HCD + 13.5% LE + Exe. Hepatic TG concentration, lipogenic genes, and total FAs were measured on day 8.Results: Oil Red O staining and TG quantification showed hepatic TG accumulation on day 8; the addition of 13.5% LE either with or without Exe suppressed the TG accumulation compared with HCD (P < 0.005). With the use of quantitative reverse transcriptase-polymerase chain reaction analysis, the expression concentrations of lipogenic genes [ATP-citrate lyase, acetyl coenzyme A carboxylase 1, FA synthase (Fasn), and stearoyl coenzyme A desaturase 1 (Scd1)] in the HCD + 13.5% LE group were 26-60% of HCD (P < 0.01) and 11-38% of HCD in the HCD + 13.5% LE + Exe group (P < 0.001), with interactions for Fasn and Scd1 (P < 0.05). With the use of gas chromatography-mass spectrometry analysis, the HCD + 13.5% LE group had lower monounsaturated fatty acids (38.7% of HCD) but higher polyunsaturated fatty acids (164% of HCD) (P < 0.001).Conclusions: In short-term studies designed to resemble the early dynamic stage of the development of hepatic steatosis, the addition of 13.5% LE to a liquid HCD reduced hepatic lipogenesis. Exe exerted an independent protective effect and interacted with LE to further reduce the expression of Scd1.

Ablation of aldehyde reductase aggravates carbon tetrachloride-induced acute hepatic injury involving oxidative stress and endoplasmic reticulum stress.

Aldehyde reductase (Akr1a) has been reported to be involved in the biosynthesis of ascorbic acid (AsA) in the mouse liver. Because Akr1a is expressed at high levels in the liver, we aimed to investigate the role of Akr1a in liver homeostasis by employing a carbon tetrachloride (CCl4)-induced hepatotoxicity model. Akr1a-deficient (Akr1a(-/-)) and wild-type (WT) mice were injected intraperitoneally with CCl4 and the extent of hepatic injury in the acute phase was assessed. Liver damage was heavier in the Akr1a(-/-) mice than in the WT mice. Furthermore, severe hepatic steatosis was observed in the livers of Akr1a(-/-) mice compared to WT mice and was restored to the levels in WT mice by AsA supplementation. Since the presence or absence of AsA had no effect on the decrease in CYP2E1 activity after the CCl4 treatment, it appears that AsA plays a role in the process after the bioactivation of CCl4. Biomarkers for oxidative stress and ER stress were markedly increased in the livers of Akr1a(-/-) mice and were effectively suppressed by AsA supplementation. Based on these collective results, we conclude that Akr1a exerts a protective effect against CCl4-induced hepatic steatosis by replenishing AsA via its antioxidative properties.

[Clinical features and gene mutations in a patient with multiple aeyl-CoA dehydrogenase deficiency with severe fatty liver].

OBJECTIVE: To analyze the clinical features and gene mutations in an adolescent patient affected with late-onset multiple aeyl-CoA dehydrogenase deficiency (MADD) with severe fatty liver. METHODS: Potential mutations of the ETFDH gene were detected with polymerase chain reaction (PCR) and DNA sequencing. RESULTS: The 13-year-and-10-month girl has presented with weakness without any other special manifestation. Laboratory tests demonstrated an elevation of myocardial enzyme levels, total cholesterol, lactic acid and abnormal serum free fatty acids. H magnetic resonance spectroscopy revealed severe fatty liver. An increase in multiple plasma acyl-carnitines was detected by gas chromatography/mass spectrometry and isobutyrylglycine in urine by screening with tandem mass spectrometry. Genetic analysis demonstrated 2 heterozygous missense mutations c.250G>A (p.Ala84Thr) and c.353G>T (p.Cys118Phe) in the ETFDH gene. The diagnosis of MADD was confirmed. The patient was given large dose of vitamin B2, which resulted in rapid clinical and biochemical improvement. CONCLUSION: A common mutation c.250G>A and a novel mutation c.353G>T in the ETFDH gene were identified in the patient. The pathogenic role of c.353G>T (p.Cys118Phe) deserves further study. Early diagnosis of MADD and appropriate therapy is crucial for the prognosis.

Estudio del efecto de la técnica aislada de bombeo del hígado, sobre las enzimas hepáticas de pacientes afectados con esteatosis hepática no-alcohólica (EHNA) / No disponible

Introducción: La Esteatosis Hepática No-Alcohólica (EHNA) se caracteriza por la excesiva acumulación de grasas en el hígado. Es una patología silenciosa, donde el 90% de los afectados son asintomáticos. Tiene mayor prevalencia en individuos obesos, diabéticos y con hiperlipidemia. Actualmente su tratamiento consiste en fármacos, dietas equilibradas y actividad física regular. No hay en publicaciones disponibles, ninguna evidencia de la actuación de la Osteopatía en la EHNA. Métodos: Se realizó un ensayo clínico aleatorio, cegado y controlado, donde la muestra ha sido compuesta por 16 individuos diagnosticados con EHNA, a través de ecografía y examen de sangre. Los sujetos fueron subdivididos en dos grupos de (N=8). El grupo experimental fue sometido a una serie de 10 bombeos del hígado, dos veces por semana, durante tres semanas. Mientras que el grupo placebo fue sometido a un simulacro del tratamiento preconizado para el grupo experimental. Al final de las 6 intervenciones, todos los sujetos fueron sometidos a nuevos exámenes de sangre. Resultados: El grupo experimental demostró una reducción significativa de las tasas enzimáticas después del tratamiento, GGT pre=66,25±39,2 y post=36,88±17,7 (p<0,008); TGO pre=41,06±21,9 y post=28,25±8,4 (p<0,045); TGP pre=97,88±60,9 y post=50,63±24,5 (p<0,017), mientras que no se observó ninguna diferencia en el grupo placebo. La serie de bombeos, la frecuencia y la duración del tratamiento mostró ser eficiente para provocar alteraciones en las tasas enzimáticas. Conclusiones: El presente estudio demostró que la técnica aislada de bombeo del hígado, realizada en series de 10 bombeos, dos veces por semana, durante tres semanas, resultó en la reducción de las tasas de las aminotransferasas GGT, TGO y TGP, de los pacientes portadores de EHNA

No disponible

[Intervention effect and mechanism of compound Ginkgo biloba preparations on nonalcoholic fatty liver].

OBJECTIVE: To investigate the intervention effect and mechanism of compound Ginkgo biloba (CGB) preparations on nonalcoholic fatty liver disease (NAFLD). METHOD: The C57BL/6 mouse NAFLD model was induced with high fat diets. Since the 2nd week after modeling, the mice were orally administered with 600 and 200 mg x kg(-1) x d(-1) CGB for eight weeks. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), cholesterol (CHOL) and LPS in serum, as well as pathological changes and expression of tumor necrosis factor-alpha (TNF-alpha) in hepatic tissues were observed. Changes in intestinal tight junction proteins ZO-1, Occludin, Claudin-1 in intestinal tissues were determined under microscopy. RESULT: Compared with the normal group, the model group showed obvious fatty degeneration in rat livers, with notable increase in TNF-alpha expression (P < 0.01), significant increases in ALT, AST, TG, CHOL and LPS in serum (P < 0.01, P < 0.05), injury in intestinal tight junction proteins, and remarkable declines in ZO-1, Occludin and Claudin-1 (P < 0.01). Compared with the model group, CGB high and low dose groups showed obvious relieves in fatty degeneration in rat livers and injury in intestinal tight junction proteins, significant reductions in TNF-alpha expression (P < 0.01, P < 0.05) and AST, TG, CHOL and LPS in serum (P < 0.01, P < 0.05) and remarkable increases in ZO-1 and Occludin expressions (P < 0.05). CONCLUSION: CGB can protect intestinal tight junction proteins, reduce intestinal leakage, relieve fatty degeneration and inflammations in livers and prevent NAFLD occurrence and development.

The hepatoprotective effect of aqueous extracts of Penthorum chinense Pursh against acute alcohol-induced liver injury is associated with ameliorating hepatic steatosis and reducing oxidative stress.

The aim of the present study was to evaluate the effects of Penthorum chinense Pursh (PCP), a health food and folk medicine, against acute alcohol-induced liver injury and further to elucidate its probable mechanisms. Male C57BL/6 mice were treated with an aqueous extract of PCP (5.2 and 10.3 g per kg BW) once daily for 7 consecutive days prior to ethanol gavage (4.7 g kg(-1)) every 12 h for a total of three doses. Pretreatment with PCP significantly decreased the elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic triglyceride after the last ethanol administration. PCP suppressed the elevation of the malondialdehyde (MDA) level, restored the glutathione (GSH) level and enhanced the activities of superoxide dismutase (SOD) and catalase (CAT) in both the serum and liver, which were associated with the inhibition of hepatic cytochrome P450 2E1 (CYP2E1). In addition, alcohol exposure markedly induced the lipolysis of white adipose tissue (WAT) through up-regulating protein expressions of adipose triglyceride lipase (ATGL) and phosphorylation of hormone-sensitive lipase (p-HSL), and enhancing the fatty acid uptake capacity in the liver by elevated hepatic CD36 expression, which were attenuated by PCP treatment. These data demonstrated that pre-treatment with PCP protected against acute ethanol-induced liver injury, possibly by reducing CYP2E1-dependent oxidative stress and ameliorating dysfunctional WAT derived-fatty acid influx to the liver. Our findings suggest that PCP might be a promising agent for the prevention of acute alcohol-induced liver injury.

Dehydroepiandrosterone sulfate and cytochrome P450 inducers alleviate fatty liver in male rats fed an orotic acid-supplemented diet.

The effects of the peroxisome proliferator, dehydroepiandrosterone sulfate (DHEAS), and the typical cytochrome P450 (CYP) inducers phenobarbital (PB) and 3-methylcholanthrene (3-MC) on fatty liver were examined in rats. Treating rats with orotic acid caused marked accumulation of lipid droplets in the liver. This effect of orotic acid was almost eradicated by co-treatment with DHEAS and PB. While DHEAS or PB alone also alleviated fatty liver, treatment with 3-MC caused little effect on a reduction in lipid droplets. Histopathological examinations revealed numerous peroxisomes in the liver of rats treated with DHEAS. In addition, a significant increase in the expression on hepatic CYPs was observed in rats the fatty liver of which was attenuated. Regarding other enzymes associated with hepatic fatty acid oxidation, the expression levels of sirtuin 1, sirtuin 6, and carnitine palmitoyltransferase 1 were also upregulated most markedly by treatment with DHEAS alone. Thus, the attenuation in fatty liver observed in the present study is likely due to peroxisome proliferation and the induction of fatty acid-metabolizing enzymes by DHEAS and typical CYP inducers.

Purified anthocyanins from bilberry and black currant attenuate hepatic mitochondrial dysfunction and steatohepatitis in mice with methionine and choline deficiency.

The berries of bilberry and black currant are a rich source of anthocyanins, which are thought to have favorable effects on nonalcoholic steatohepatitis (NASH). This study was designed to examine whether purified anthocyanins from bilberry and black currant are able to limit the disorders related to NASH induced by a methionine-choline-deficient (MCD) diet in mice. The results showed that treatment with anthocyanins not only alleviated inflammation, oxidative stress, steatosis, and even fibrosis but also improved depletion of mitochondrial content and damage of mitochondrial biogenesis and electron transfer chain developed concomitantly in the liver of mice fed the MCD diet. Furthermore, anthocyanins treatment promoted activation of AMP-activated protein kinase (AMPK) and expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α). These data provide evidence that anthocyanins possess significant protective effects against NASH and mitochondrial defects in response to a MCD diet, with a mechanism maybe through affecting the AMPK/PGC-1α signaling pathways.

Fructose supplementation impairs rat liver autophagy through mTORC activation without inducing endoplasmic reticulum stress.

Supplementation with 10% liquid fructose to female rats for 2weeks caused hepatic steatosis through increased lipogenesis and reduced peroxisome proliferator activated receptor (PPAR) α activity and fatty acid catabolism, together with increased expression of the spliced form of X-binding protein-1 (Rebollo et al., 2014). In the present study, we show that some of these effects are preserved after sub-chronic (8weeks) fructose supplementation, specifically increased hepatic expression of lipid synthesis-related genes (stearoyl-CoA desaturase, ×6.7-fold; acetyl-CoA carboxylase, ×1.6-fold; glycerol-3-phosphate acyltransferase, ×1.65-fold), and reduced fatty acid ß-oxidation (×0.77-fold), resulting in increased liver triglyceride content (×1.69-fold) and hepatic steatosis. However, hepatic expression of PPARα and its target genes was not modified and, further, livers of 8-week fructose-supplemented rats showed no sign of unfolded protein response activation, except for an increase in p-IRE1 levels. Hepatic mTOR phosphorylation was enhanced (×1.74-fold), causing an increase in the phosphorylation of UNC-51-like kinase 1 (ULK-1) (×2.8-fold), leading to a decrease in the ratio of LC3B-II/LC3B-I protein expression (×0.39-fold) and an increase in the amount of the autophagic substrate p62, indicative of decreased autophagy activity. A harmful cycle may be established in the liver of 8-week fructose-supplemented rats where lipid accumulation may cause defective autophagy, and reduced autophagy may result in decreased free fatty acid formation from triglyceride depots, thus reducing the substrates for ß-oxidation and further increasing hepatic steatosis. In summary, the length of supplementation is a key factor in the metabolic disturbances induced by fructose: in short-term studies, PPARα inhibition and ER stress induction are critical events, whereas after sub-chronic supplementation, mTOR activation and autophagy inhibition are crucial.

Últimos avances en páncreas y vías biliares / Pancreas and biliary tract: recent developments

La pancreatitis aguda (PA) es una enfermedad frecuente, asociada a una importante morbilidad y con una mortalidad considerable. En el presente artículo se revisan las novedades acerca de esta enfermedad presentadas en la Digestive Disease Week 2014. La esteatosis pancreática podría ser causa de PA recurrente. Los pacientes con diabetes mellitus tienen una incidencia aumentada de PA y cáncer de páncreas. El uso de fármacos anti-TNF en la enfermedad inflamatoria intestinal podría proteger frente al desarrollo de PA. La presencia de pancreas divisum protege frente a PA de origen biliar. El sistema PANCODE, para describir complicaciones locales de PA, tiene una buena variabilidad interobservador adaptada a las nuevas definiciones de la clasificación revisada de Atlanta. El uso de antibioterapia profiláctica precoz en PA predispone al desarrollo de infecciones intraabdominales fúngicas. El secuestro de fluidos en PA se asocia a edad joven, etiología alcohólica y criterios de síndrome de respuesta inflamatoria sistémica. La causa más frecuente de mortalidad en PA es el fallo multiorgánico precoz, no la infección de necrosis pancreática. Pacientes con PA y déficit de vitamina D podrían beneficiarse de suplementos de esta vitamina. La administración moderada de fluidos en urgencias (500 a 1.000 ml) podría asociarse a mejor evolución de PA

Acute pancreatitis (AP) is a common disease that is associated with significant morbidity and considerable mortality. In this article, developments relating to this disease that were presented in DDW 2014 are reviewed. Pancreatic steatosis could be a cause of recurrent AP. Patients with DM have an increased incidence of AP and pancreatic cancer. The use of anti-TNF drugs in inflammatory bowel disease may protect against the occurrence of AP. The presence of pancreas divisum protects against acute biliary pancreatitis. The PANCODE system for describing local complications of AP has good interobserver agreement, when the new definitions of the revised Atlanta classification are applied. The use of prophylactic antibiotics in early-stage AP predisposes the development of intra-abdominal fungal infections. Fluid sequestration in AP is linked with young age, alcoholism and indicators of systemic inflammatory response syndrome. The most common cause of mortality in AP is early onset of multiple organ failure, not pancreatic necrosis infection. Patients with AP and vitamin D deficiency could benefit from taking vitamin D supplements. Moderate fluid administration in emergencies (500-1000 mL) could be associated with better AP development

Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice.

The potential role of endogenously synthesized PUFAs is a highly overlooked area. Elongation of very long-chain fatty acids (ELOVLs) in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2(-/-) mice displayed substantially decreased levels of 22:6(n-3), DHA, and 22:5(n-6), docosapentaenoic acid (DPA) n-6, and an accumulation of 22:5(n-3) and 22:4(n-6) in both liver and serum, showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24-carbon precursors for DHA and DPAn-6 formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol-regulatory element binding protein 1c (SREBP-1c), as well as its downstream target genes. Surprisingly, the Elovl2(-/-) mice were resistant to hepatic steatosis and diet-induced weight gain, implying that hepatic DHA synthesis via ELOVL2, in addition to controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP-1c-independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA.

Obesity resistance and deregulation of lipogenesis in Δ6-fatty acid desaturase (FADS2) deficiency.

Δ-6-fatty acid desaturase (FADS2) is the key enzyme in the biosynthesis of polyunsaturated fatty acids (PUFAs), the essential structural determinants of mammalian membrane lipid-bilayers. We developed the auxotrophic fads2(-/-) mouse mutant to assess the enigmatic role of ω3- and ω6-PUFAs in lipid homeostasis, membrane structure and function. Obesity resistance is another major phenotype of the fads2(-/-) mutant, the molecular basis of which is unknown. Phospholipidomic profiling of membrane systems of fads2(-/-)mice revealed diacylglycerol-structures, deprived of PUFAs but substituted with surrogate eicosa-5,11,14-trienoic acid. ω6-Arachidonic (AA) and ω3-docosahexaenoic acid (DHA) supplemented diets transformed fads2(-/-) into AA-fads2(-/-) and DHA-fads2(-/-) mutants. Severely altered phospholipid-bilayer structures of subcellular membranes of fads2(-/-) liver specifically interfered with maturation of transcription factor sterol-regulatory-element-binding protein, the key regulator of lipogenesis and lipid homeostasis. This study strengthens the concept that specific PUFA-substituted membrane phospholipid species are critical constituents of the structural platform operative in lipid homeostasis in normal and disease conditions.

Sesame oil attenuates nutritional fibrosing steatohepatitis by modulating matrix metalloproteinases-2, 9 and PPAR-γ.

Sesame oil is a nutrient-rich antioxidant popular in alternative medicine. It contains sesamin, sesamol, and sesamolin, all of which contribute to its improved liver function in various animal model studies. However, its effect on nutritional fibrosing steatohepatitis is unclear. We investigated therapeutic sesame oil on matrix metalloproteinases-2, 9 (MMP-2, 9) in nutritional fibrosing steatohepatitic mice. C57BL/6 J mice were fed with methionine-choline deficient (MCD) diet for 35 days to induce fibrosing steatohepatitis. Sesame oil was treated from 29-35th day. Body weight, steatosis, aspartate transaminase, alanine transaminase, peroxisome proliferator-activated receptor (PPAR)-γ, α-smooth muscle actin (α-SMA), MMP-2, 9, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 were assessed after 35 days. All tested parameters except TIMP-1 and PPAR-γ were higher in MCD fed mice than in normal control mice. Mice fed with MCD diet for 4 weeks showed severe liver injury with steatosis, necrotic-inflammation, and fibrosis. In sesame-oil (4 ml)-treated mice, all tested parameters except TIMP-1, α-SMA, and PPAR-γ were significantly attenuated compared with MCD fed mice. Sesame oil inhibited MMP-2, 9 activities, but up-regulated TIMP-1 expression in MCD fed mice. In addition, a histological analysis of liver tissue samples showed that sesame oil provided significant protection against fibrosis. We conclude that therapeutic sesame oil protects against fibrosing steatohepatitis by inhibiting MMP-2, 9 activities, up-regulating TIMP-1 expression, and PPAR-γ.