Reduced Lipid Synthesis Research Articles

Therapeutic potential of buckwheat hull flavonoids in db/db mice, a model of type 2 diabetes

In this study, the therapeutic effects of buckwheat hull flavonoids (BHFs) on type 2 diabetes db/db mice were investigated. After administration by BHFs nine weeks, body weight, visceral index, biochemical indicators in serum and in liver were detected. The liver pathological changes were observed under microscopic observations. Real-time quantitative PCR was used to detect IRS-1, PI3kα, AKT2, SREBP-1c, FAS, ACC1 mRNA expression in liver. The results showed that insulin resistance significantly reduced after the BHFs treatment. BHFs could reduce the TG, TC, vLDL-c, FFA levels in serum and TG, TC levels in liver and potentiate insulin resistance-related PI3k/AKT2 signal pathway and down-regulated SREBP-1c, FAS, ACC1 mRNA in the liver tissue of db/db mice. Moreover, BHFs could significantly alleviate the structure disorder of liver. The protective effect of BHFs on T2DM may be mediated by facilitating PI3k/AKT signal pathway and down-regulating SREBP-1c, FAS and ACC1 mRNA expression to reduce lipid synthesis.

Mineralocorticoid antagonism enhances brown adipose tissue function in humans: A randomized placebo-controlled cross-over study.

To investigate whether mineralocorticoid (MC) antagonism enhances brown adipose tissue (BAT) function in humans. In a randomized double-blind, cross-over designed trial, 10 healthy adults (two men, eight women) underwent 2 weeks of spironolactone (100 mg/d) treatment and placebo, with an intervening 2-week wash-out period. BAT function was assessed in response to cooling and to a mixed meal. Metabolic activity was measured by fluoro-deoxyglucose (FDG) uptake (maximal standardized uptake value, SUVmax ) using PET-CT. Thermogenic activity was measured by skin temperatures overlying supraclavicular (SCL) BAT depots using infrared thermography. Postprandial metabolism was measured by energy production rate (EPR) and lipid synthesis using indirect calorimetry. During cooling, BAT metabolic activity (SUV 6.30 ± 2.16 vs 3.98 ± 1.34; P < 0.05) and volume (54.9 ± 22.8 vs 21.6 ± 11.8 cm3 ; P < 0.05) were significantly higher, and mean SCL temperature decreased by a smaller degree (-0.3°C°± 0.2°C vs -0.9°C ± 0.2°C; P = 0.05) with spironolactone treatment. A mixed meal increased SCL temperature and EPR. The postprandial rise in SCL temperature (+0.4°C ± 0.1°C vs +0.1°C ± 0.1°C; P < 0.05) but not in EPR was greater during spironolactone treatment. Postprandial lipid synthesis occurred in three participants with placebo but in none with spironolactone treatment (P = 0.06). MC antagonism enhanced human BAT function in response to cooling and to a meal during which lipid synthesis was suppressed. As postprandial EPR comprises energy dissipated as heat and energy required to store nutrients, the reduction in lipid synthesis during MC antagonism is a probable consequence of concurrent stimulation of BAT thermogenesis. The shift in energy usage from storage to heat dissipation indicates that MC antagonists may have therapeutic benefit for obesity.

Insights into a Possible Mechanism Underlying the Connection of Carbendazim-Induced Lipid Metabolism Disorder and Gut Microbiota Dysbiosis in Mice.

Carbendazim (CBZ), a systemic, broad-spectrum benzimidazole fungicide, is widely used to control fungal diseases and has been regarded as an endocrine disruptor that causes mammalian toxicity in different target organs. Here, we discovered that chronic administrations of CBZ at 0.2, 1, and 5 mg/kg body weight for 14 weeks not only changed the composition of gut microbiota but also induced significant increases in body, liver, and epididymal fat weight in mice. At the biochemical level, the serum triglyceride (TG) and glucose levels also increased after CBZ exposure. Moreover, the level of serum lipoprotein lipase (LPL), which plays an important role in fatty acid release from TG, was decreased significantly. For gut microbiota, 16S rRNA gene sequencing and real-time qPCR revealed that CBZ exposure significantly perturbed the mice gut microbiome, and gas chromatography found that the production of short-chain fatty acids were altered. Moreover, CBZ exposure increased the absorption of exogenous TG in the mice intestine and inhibited the TG consumption, eventually leading the serum triglyceride to maintain higher levels. The increase of lipid absorption in the intestine direct caused hyperlipidemia and the multi-tissue inflammatory response. In response to the rise of lipid in blood, the body maintains the balance of lipid metabolism in mice by reducing lipid synthesis in the liver and increasing lipid storage in the fat. Chronic CBZ exposure induced the gut microbiota dysbiosis and disturbed lipid metabolism, which promoted the intestinal absorption of excess triglyceride and caused multiple tissue inflammatory responses in mice.

Fucosylated chondroitin sulfate oligosaccharides from Isostichopus badionotus regulates lipid disorder in C57BL/6 mice fed a high-fat diet

Fucosylated chondroitin sulfate (fCS) and its depolymerized derivative (DfCS), prepared from sea cucumbers, are well-known for their anticoagulant activity. However, their other functional activities are poorly understood. Recently, we obtained fCS oligosaccharides from Isostichopus Badionotus by a modified controllable Fenton-system, named as DfCS-Ib. The functional activities of these oligosaccharides are still unclear. The present study investigated anti-hyperlipidemic activity of DfCS-Ib using a high-fat diet (HFD)–fed mice model. The results indicated that DfCS-Ib reduced obesity, hyperlipidemia, and inflammation caused by HFD. Meanwhile, DfCS-Ib increased the mRNA expression of PPARγ and decreased the mRNA expression of leptin, aP2, and F4/80 in fat tissue. Transcriptome analysis indicated that DfCS-Ib normalized the expressions of genes regulating lipid metabolism. Our results suggested that DfCS-Ib can alleviated lipid disorder by reducing lipid synthesis and promoting lipid lipidolysis. DfCS-Ib can act as a functional agent to regulate lipid disorder.

Methyl ferulic acid attenuates ethanol-induced hepatic steatosis by regulating AMPK and FoxO1 Pathways in Rats and L-02 cells

Methyl ferulic acid (MFA) is a biologically active monomer extracted and purified from the Chinese herbal medicine Securidaca inappendiculata hasskarl. The previously studies showed that MFA improved acute liver injury induced by ethanol. However, the effect of MFA on ethanol-induced hepatic steatosis in alcoholic liver disease (ALD) still remains unclear. The current study was aimed at elucidating the effect of MFA on alcohol-induced hepatic steatosis and the underlying mechanisms. Human hepatocyte L-02 cells exposed to 200 mM ethanol for 24 h to simulate alcoholic steatosis in vitro. SD rats were fed a Lieber-DeCarli diet containing 5% (w/v) alcohol for 16 weeks to induce alcoholic liver disease in vivo. We examined the effect of MFA on ethanol-induced lipid deposition in L-02 cells and SD rats. The results showed that MFA reduced the accumulation of lipid in L-02 cells, improved alcoholic liver injury in rats, alleviated hepatic pathological lesions, and reduced lipid deposition in rat serum and liver. Further studies suggest that MFA reduces lipid synthesis by activating AMPK-ACC/MAPK-FoxO1 pathway. In addition, MFA also promotes lipid oxidation by up-regulating the expression of SIRT1, PPAR-α, and CPT-1α. Taken together, MFA ameliorates ethanol-induced hepatic steatosis by activating AMPK-ACC/MAPK-FoxO1 pathway and up-regulating the expression levels of SIRT1, PPAR-α, and CPT-1α.

Design, synthesis and biological evaluation of novel bouchardatine analogs as potential inhibitors of adipogenesis/lipogenesis in 3T3-L1 adipocytes

Inhibition of the differentiation of adipocytes and reduced lipid synthesis are efficacious approaches for treating obesity-related metabolic disorders. Bouchardatine (Bou) is a natural alkaloid that has been reported to moderately inhibit the differentiation of 3T3-L1 cells without inducing toxicity. To explore the importance of aldehyde group at 8a-position of Bou and optimize the activity, we synthesized 35 (31 novel) compounds by discarding or replacing aldehyde group with halogen and introducing different amine chains at 5-position of Bou. The lipid-lowering activity was evaluated using a cell-based screening system. The substitution of the group at the 8a-position of compounds was important for its lipid-lowering activity, and the SAR was discussed. The selective compound 6e showed a 93-fold increase in its lipid-lowering effect (EC50 = 0.24 μM) compared with Bou (EC50 ≈ 25 μM). Further mechanistic studies revealed that compound 6e activated AMP-activated protein kinase (AMPK) pathway and inhibited MCE activity to block cell proliferation and induce cell cycle arrest at the early stage of differentiation, thus decreasing the expression of adipogenic factors and fatty acid synthesis-related proteins.

(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis

An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin-angiotensin system. To investigate the physiological role of (P)RR in lipid metabolism in vivo. We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol). Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6 mice fed a normal- or high-fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that (P)RR inhibition decreased protein abundance of ACC (acetyl-CoA carboxylase) and PDH (pyruvate dehydrogenase). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic (P)RR inhibition attenuated diet-induced obesity and hepatosteatosis. Collectively, our study suggests that (P)RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.

Glucose-6-phosphate dehydrogenase and transketolase modulate breast cancer cell metabolic reprogramming and correlate with poor patient outcome.

The pentose phosphate pathway is a fundamental metabolic pathway that provides cells with ribose and NADPH required for anabolic reactions — synthesis of nucleotides and fatty acids — and maintenance of intracellular redox homeostasis. It plays a key role in tumor metabolic reprogramming and has been reported to be deregulated in different types of tumors. Herein, we silenced the most important enzymes of this pathway — glucose-6-phosphate dehydrogenase (G6PD) and transketolase (TKT) — in the human breast cancer cell line MCF7. We demonstrated that inhibition of G6PD, the oxidative branch-controlling enzyme, reduced proliferation, cell survival and increased oxidative stress. At the metabolic level, silencing of both enzymes reduced ribose synthesis. G6PD silencing in particular, augmented the glycolytic flux, reduced lipid synthesis and increased glutamine uptake, whereas silencing of TKT reduced the glycolytic flux. Importantly, we showed using breast cancer patient datasets that expression of both enzymes is positively correlated and that high expression levels of G6PD and TKT are associated with decreased overall and relapse-free survival. Altogether, our results suggest that this metabolic pathway could be subjected to therapeutic intervention to treat breast tumors and warrant further investigation.

Combined exploitation of CO2 and nutrient replenishment for increasing biomass and lipid productivity of the marine diatoms Thalassiosira weissflogii and Cyclotella cryptica

Diatoms are promising candidates for sustainable production of biofuels but their use is restricted due to the difficulties of combining high-biomass productivity and lipid accumulation. Here, we report the effect of high levels of nutrients and supplementation of 10% CO2 on biomass and lipid productivity of the marine diatoms Thalassiosira weissflogii and Cyclotella cryptica. Daily nutrient replenishment stimulated growth and increased the biomass but reduced lipid synthesis and dropped the level of triglycerides (TAG) close to zero. On the contrary, addition of 10% CO2 (v/v) doubled or tripled lipid content in comparison with air-sparged cultures, but induced only a modest increase of biomass. Assessment of the content in carbohydrates, lipids, and proteins suggested that CO2 stimulated lipogenesis from carbohydrates in both diatoms. In order to combine these effects, we also tested a two-stage cultivation that alternated nutrient replenishment together with addition of CO2 during nutrient shortage. T. weissflogii and C. cryptica responded to these conditions by increasing dry biomass to 1.25 g L−1 without reduction of total lipid percentage. In both species, TAG became the main lipid component and accounted for more than 60% of total glycerolipids in C. cryptica. These results underline the metabolic plasticity of diatom cells and indicate a possible way to maximize the production of biomass and functional products by tuning culture conditions.

Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming.

Tumor cells reprogram their metabolism to survive and grow in a challenging microenvironment. Some of this reprogramming is performed by epigenetic mechanisms. Epigenetics is in turn affected by metabolism; chromatin modifying enzymes are dependent on substrates that are also key metabolic intermediates. We have shown that the chromatin remodeling enzyme Brahma-related gene 1 (BRG1), an epigenetic regulator, is necessary for rapid breast cancer cell proliferation. The mechanism for this requirement is the BRG1-dependent transcription of key lipogenic enzymes and regulators. Reduction in lipid synthesis lowers proliferation rates, which can be restored by palmitate supplementation. This work has established BRG1 as an attractive target for breast cancer therapy. Unlike genetic alterations, epigenetic mechanisms are reversible, promising gentler therapies without permanent off-target effects at distant sites.

Liver Regeneration Is Impaired in Mice with Acute Exposure to a Very Low Carbohydrate Diet.

The metabolic response to hepatic insufficiency has been implicated in the regulators of normal liver regeneration. Modulation of nutritional factors has been demonstrated to affect liver regeneration. Diets containing very low carbohydrate and high fat levels cause a unique metabolic state, the effect of which on liver regeneration is unknown. Mice were placed on standard mice chow (ND) or a very low carbohydrate diet (VLCD) after 70% partial hepatectomy (PH). After 48h, mice on VLCD were placed back to ND. The serum metabolic profiles, hepatic lipid content, and gene expression profile were examined. The dynamics of liver regeneration were detected at timed points. Activation of signaling pathways was examined. VLCD feeding caused hypoglycemia and elevation of serum β-hydroxybutyrate and free fatty acids in mice after PH. It increased hepatic triglyceride contents, enhanced fatty acid oxidation, and reduced lipid synthesis. Mice on VLCD exhibited diminished hepatocellular mitotic frequency, a reduced BrdU incorporation and liver mass regeneration ratio, and delayed expression of PCNA. Expressions of IL-6 and TNFα in liver and serum were downregulated. Meanwhile, phosphorylation of STAT3, Erk, and AKT was delayed compared with controls. VLCD feeding delayed liver regeneration, probably because of the suppression of TNFα-IL-6-STAT3 signaling and delayed activation of Erk and AKT induced by the unique metabolic effects of this diet.

The Influence of Two Different Foam Creams on Skin Barrier Repair of Foot Xerosis: A Prospective, Double-Blind, Randomised, Placebo-Controlled Intra-Individual Study

Background/Aims: Dry skin, or xerosis, is a common condition and a key feature of skin diseases like atopic dermatitis (AD) and ichthyosis vulgaris. Foot xerosis may exist without underlying disease and could be related to very mild forms of AD or ichthyosis vulgaris. The synthesis of important skin lipids (cholesterol, free fatty acids and ceramides) is reduced in xerosis and AD, and reduced lipid synthesis is responsible for a lack of lipids and enzymes in the skin barrier. This slows down reorganisation of the lipid lamellae in the stratum corneum (SC). Methods: Skin barrier integrity was measured by morphometric analysis of the lipid lamellae in the SC after 4 weeks of treatment with a foam cream (active agent vs. placebo). Results: Significant treatment effects were shown after 2 and 4 weeks by an increasing amount of intercellular lipids in the SC. Conclusion: This study shows that a quick reorganisation of the SC lipids initiates a good restoration of the whole skin barrier after 4 weeks of treatment with a foam cream.

MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice

High plasma cholesterol levels are a major risk factor for atherosclerosis. Plasma cholesterol can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. Previously we showed that lentivirally mediated hepatic expression of microRNA-30c (miR-30c) reduced hyperlipidemia and atherosclerosis in mice without causing hepatosteatosis. Because viral therapy would be formidable, we examined whether a miR-30c mimic can be used to mitigate hyperlipidemia and atherosclerosis without inducing steatosis. Delivery of a miR-30c mimic to the liver diminished diet-induced hypercholesterolemia in C57BL/6J mice. Reductions in plasma cholesterol levels were significantly correlated with increases in hepatic miR-30c levels. Long term dose escalation studies showed that miR-30c mimic caused sustained reductions in plasma cholesterol with no obvious side effects. Furthermore, miR-30c mimic significantly reduced hypercholesterolemia and atherosclerosis in Apoe(-/-) mice. Mechanistic studies showed that miR-30c mimic had no effect on LDL clearance but reduced lipoprotein production by down-regulating microsomal triglyceride transfer protein expression. MiR-30c had no effect on fatty acid oxidation but reduced lipid synthesis. Additionally, whole transcriptome analysis revealed that miR-30c mimic significantly down-regulated hepatic lipid synthesis pathways. Therefore, miR-30c lowers plasma cholesterol and mitigates atherosclerosis by reducing microsomal triglyceride transfer protein expression and lipoprotein production and avoids steatosis by diminishing lipid syntheses. It mitigates atherosclerosis most likely by reducing lipoprotein production and plasma cholesterol. These findings establish that increasing hepatic miR-30c levels is a viable treatment option for reducing hypercholesterolemia and atherosclerosis.

Hypolipidemic Activity of Peony Seed Oil Rich in α-Linolenic, is Mediated Through Inhibition of Lipogenesis and Upregulation of Fatty Acid β-Oxidation.

Peony seed oil (PSO) is a new resource food rich in α-Linolenic Acid(ALA) (38.66%). The objective of this study was to assess the modulatory effect of PSO on lipid metabolism. Lard oil, safflower oil (SFO), and PSO were fed to wistar rats with 1% cholesterol in the diet for 60 d. Serum and liver lipids showed significant decrease in total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C) levels in PSO fed rats compared to lard oil and SFO fed rats. ALA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), contents were significantly increased, whereas linoleic acid (LA), arachidonic acid (AA) levels decreased in serum and liver of PSO fed rats. Feeding PSO increased ALA level and decreased n-6 to n-3 polyunsaturated fatty acid (PUFA) ratio. The hypolipidemic result of PSO indicated that PSO participated in the regulation of plasma lipid concentration and cholesterol metabolism in liver. The decreased expression of sterol regulatory element-binding proteins 1C (SREBP-1c), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS)-reduced lipid synthesis; Activation of peroxisome proliferator-activator receptor (PPARα) accompanied by increase of uncoupling protein2 (UP2) and acyl-CoA oxidase (AOX) stimulated lipid metabolism and exerted an antiobesity effect via increasing energy expenditure for prevention of obesity.

Benzo(a)pyrene induces interleukin (IL)-6 production and reduces lipid synthesis in human SZ95 sebocytes via the aryl hydrocarbon receptor signaling pathway.

In this study, we determined the effects of benzo(a)pyrene (BaP) on the expression of aryl hydrocarbon receptor (AhR) and cytochrome P450 1A1 (CYP1A1), and assessed the action of BaP on inflammatory cytokine expression and lipid synthesis in SZ95 sebocytes in vitro. BaP (10(-8), 10(-7), 10(-6) and 10(-5)M) was not cytotoxic for SZ95 sebocytes after 24h exposure. Expression of AhR was promoted in mRNA lever, while was inhibited in protein lever after BaP (10(-5)M) exposure. CYP1A1 expression was up-regulated in both mRNA and protein levels. BaP (10(-5)M) exerted a stimulatory action on interleukin (IL)-6 secretion, while a dose-dependently inhibitory effect on lipid synthesis from 10(-8)M to 10(-5)M in SZ95 sebocytes. Both actions were partly antagonized in AhR-knockdowned SZ95 sebocytes. This study demonstrates that BaP can activate AhR signaling pathway, and exhibits pro-inflammatory effects and inhibitory effects on sebum production in human sebocytes.

Adaptations of lipid metabolism and food intake in response to low and high fat diets in juvenile grass carp (Ctenopharyngodon idellus)

This study was conducted to examine the systemic metabolic strategies of grass carp to maintain lipid homeostasis when fed with low- or high-fat diets. The isonitrogenous diets with different fat levels (9.3, 48.7 and 107.9gkg−1) were fed to grass carp for 8weeks. After the feeding trial, the growth rate and feed intake of grass carp fed with low-lipid (LL) diet or high-lipid (HL) diet were lower than fish fed with medium-lipid (ML) diet. Serum triglyceride (TG) and total body fat contents were significantly increased in grass carp with increasing lipid intake. Gene expression data indicated that fish increased hepatic gk and pk expressions to elevate glycolysis, and enhanced acc and fas expressions to accelerate biosynthesis of fatty acid (FA) to adapt to low lipid intake. Meanwhile, fish fed with LL diet decreased hepatic cpt1 expression to depress lipolysis, leading to low contents of serum TG and body fat. In contrast, excess lipid intake increased g6pase, pepck and pparα expressions to stimulate gluconeogenesis and β-oxidative, while decreased acc and fas expressions to reduce lipid synthesis in fish liver. Moreover, increased β-oxidative-induced FA or gluconeogenesis-induced serum glucose might induce the appetite suppression by high dietary fat through modulation of leptin expression. This study could be a reference in the systemic adaptation of lipid metabolism responding to dietary fat in fish. Statement of relevanceSystemic adaptation of lipid metabolism responding to dietary lipid.

Effect of Dietary Fat on Gene Expression in Poultry, A Review.

Traditionally, poultry farmers aimed to produce birds with high body weight and feed conversion ratio. However, in line with current developments, there are other traits that must be taken into account as well. These include producing poultry meat with lower body fat content and improving the nutritional quality of the poultry meat to appeal to consumer requirements. The interrelated importance of human diet and health status is an ancient subject. Human foods as a lifestyle factor is involved in the incidence of many types of diseases, such as cardiovascular diseases and cancer. Recent reports suggest that not only the quantity but also the composition of dietary fat is an important factor to prevent these metabolic diseases in human populations. It has been reported that some dietary fats are able to reduce lipid synthesis and increase fatty acid oxidation and diet-mediated thermogenesis. The outcome of this change is a superior animal product with lower fat content. There is evidence of dissimilar mechanisms of action of n-3 and n-6 fatty acids. Dietary fatty acids have various effects on cellular metabolism, and many of these effects are carried out through the alteration of gene expression. This review will focus on the control of body fat by gene expression in avians.

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

Adipose triglyceride lipase (ATGL) initiates intracellular triglyceride (TG) catabolism. In humans, ATGL deficiency causes neutral lipid storage disease with myopathy (NLSDM) characterized by a systemic TG accumulation. Mice with a genetic deletion of ATGL (AKO) also accumulate TG in many tissues. However, neither NLSDM patients nor AKO mice are exceedingly obese. This phenotype is unexpected considering the importance of the enzyme for TG catabolism in white adipose tissue (WAT). In this study, we identified the counteracting mechanisms that prevent excessive obesity in the absence of ATGL. We used "healthy" AKO mice expressing ATGL exclusively in cardiomyocytes (AKO/cTg) to circumvent the cardiomyopathy and premature lethality observed in AKO mice. AKO/cTg mice were protected from high-fat diet (HFD)-induced obesity despite complete ATGL deficiency in WAT and normal adipocyte differentiation. AKO/cTg mice were highly insulin sensitive under hyperinsulinemic-euglycemic clamp conditions, eliminating insulin insensitivity as a possible protective mechanism. Instead, reduced food intake and altered signaling by peroxisome proliferator-activated receptor-gamma (PPAR-γ) and sterol regulatory element binding protein-1c in WAT accounted for the phenotype. These adaptations led to reduced lipid synthesis and storage in WAT of HFD-fed AKO/cTg mice. Treatment with the PPAR-γ agonist rosiglitazone reversed the phenotype. These results argue for the existence of an adaptive interdependence between lipolysis and lipid synthesis. Pharmacological inhibition of ATGL may prove useful to prevent HFD-induced obesity and insulin resistance.

Preventive effect of total glycosides from Ligustri Lucidi Fructus against nonalcoholic fatty liver in mice.

The protective effects of the total glycosides from Ligustri Lucidi Fructus against nonalcoholic fatty liver (NAFL) in mice were investigated. Liver injury was induced by the administration of high fat diet for 60 days. During this period, the model group received high fat diet only; the treatment groups received various drugs plus high fat diet. Compared with the model group, the total glycosides significantly decreased the contents of triglyceride (TG) and cholesterol (TC), as well as the activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum. Moreover, the contents of TG and TC in liver tissue and the liver index were reduced. Histological findings also confirmed antisteatosis. Compared with the model group, total glycosides significantly reduced the levels of the sterol regulatory element binding protein-1c (SREBP-1c) and liver X receptor-a (LXR-α) protein, and down-regulated the expression of SREBP-1c, LXR-α and interleukin-6 (IL-6) mRNA in the liver. These results suggest that the total glycosides are effective in the treatment of NAFL of mice. Their mode of action is associated with inhibiting SREBP-1c, LXR-α and IL-6 mRNA, reducing lipid synthesis factor SREBP-1c and LXR-α protein and gene expression, suppressing inflammatory responses, then decreasing serum lipid and hepatic lipid.

Impaired self-renewal and increased colitis and dysplastic lesions in colonic mucosa of AKR1B8-deficient mice.

Ulcerative colitis and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Aldo-keto reductase 1B10 (AKR1B10) is specifically expressed in the colonic epithelium, but downregulated in colorectal cancer. This study was aimed to investigate the etiopathogenic role of AKR1B10 in ulcerative colitis and CAC. Ulcerative colitis and CAC biopsies (paraffin-embedded sections) and frozen tissues were collected to examine AKR1B10 expression. Aldo-keto reductase 1B8 (the ortholog of human AKR1B10) knockout (AKR1B8(-/-)) mice were produced to estimate its role in the susceptibility and severity of chronic colitis and associated dysplastic lesions, induced by dextran sulfate sodium (DSS) at a low dose (2%). Genome-wide exome sequencing was used to profile DNA damage in DSS-induced colitis and tumors. AKR1B10 expression was markedly diminished in over 90% of ulcerative colitis and CAC tissues. AKR1B8 deficiency led to reduced lipid synthesis from butyrate and diminished proliferation of colonic epithelial cells. The DSS-treated AKR1B8(-/-) mice demonstrated impaired injury repair of colonic epithelium and more severe bleeding, inflammation, and ulceration. These AKR1B8(-/-) mice had more severe oxidative stress and DNA damage, and dysplasias were more frequent and at a higher grade in the AKR1B8(-/-) mice than in wild-type mice. Palpable masses were seen in the AKR1B8(-/-) mice only, not in wild-type. AKR1B8 is a critical protein in the proliferation and injury repair of the colonic epithelium and in the pathogenesis of ulcerative colitis and CAC, being a new etiopathogenic factor of these diseases.