Hepatic Deletion of Mboat7 (Lpiat1) Causes Activation of SREBP-1c and Fatty Liver.
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ABSTRACT:
SUBMITTER: Xia M
PROVIDER: S-EPMC8022244 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Elongation of very long chain fatty acids (ELOVL)5 is one of seven mammalian fatty acid condensing enzymes involved in microsomal fatty acid elongation. To determine the in vivo substrates and function of ELOVL5, we generated Elovl5(-/-) mice. Studies using liver microsomal protein from wild-type and knockout mice demonstrated that the elongation of gamma-linolenic (C18:3, n-6) to dihomo-gamma-linolenic (C20:3, n-6) and stearidonic (C18:4, n-3) to omega3-arachidonic acid (C20:4, n-3) required ELOVL5 activity. Tissues of Elovl5(-/-) mice accumulated the C18 substrates of ELOVL5 and the levels of the downstream products, arachidonic acid (C20:4, n-6) and docosahexaenoic acid (DHA, C22:6, n-3), were decreased. A consequence of decreased cellular arachidonic acid and DHA concentrations was the activation of sterol regulatory element-binding protein (SREBP)-1c and its target genes involved in fatty acid and triglyceride synthesis, which culminated in the development of hepatic steatosis in Elovl5(-/-) mice. The molecular and metabolic changes in fatty acid metabolism in Elovl5(-/-) mice were reversed by dietary supplementation with arachidonic acid and DHA. These studies demonstrate that reduced ELOVL5 activity leads to hepatic steatosis, and endogenously synthesized PUFAs are key regulators of SREBP-1c activation and fatty acid synthesis in livers of mice.
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Project description:Hepatic steatosis, characterized by ectopic hepatic triglyceride accumulation, is considered as the early manifestation of non-alcoholic fatty liver diseases (NAFLD). Increased SREBP-1c level and activity contribute to excessive hepatic triglyceride accumulation in NAFLD patients; however, negative regulators of Srebp-1c are not well defined. In this study, we show that Dec1, a critical regulator of circadian rhythm, negatively regulates hepatic Srebp-1c expression. Hepatic Dec1 expression levels are markedly decreased in NAFLD mouse models. Restored Dec1 gene expression levels in NAFLD mouse livers decreased the expression of Srebp-1c and lipogenic genes, subsequently ameliorating the fatty liver phenotype. Conversely, knockdown of Dec1 expression by an adenovirus expressing Dec1-specific shRNA led to an increase in hepatic TG content in normal mouse livers. Correspondingly, expression levels of lipogenic genes, including Srebp-1c, Fas, and Acc, were increased in livers of mice with Dec1 knockdown. Moreover, a functional lipogenesis assay suggested that Dec1 overexpression repressed lipid synthesis in primary hepatocytes. Finally, a luciferase reporter gene assay indicates that DEC1 inhibits Srebp-1c gene transcription via the E-box mapped to the promoter region. Chromatin immunoprecipitation confirmed that DEC1 proteins bound to the identified E-box element. Our studies indicate that DEC1 is an important regulator of Srebp-1c expression and links circadian rhythm to hepatic lipogenesis. Activation of Dec1 can alleviate the nonalcoholic fatty liver phenotype.
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Project description:Hepatic steatosis is present in insulin-resistant obese rodents and is concomitant with active lipogenesis. Hepatic lipogenesis depends on the insulin-induced activation of the transcription factor SREBP-1c. Despite prevailing insulin resistance, SREBP-1c is activated in the livers of genetically and diet-induced obese rodents. Recent studies have reported the presence of an ER stress response in the livers of obese ob/ob mice. To assess whether ER stress promotes SREBP-1c activation and thus contributes to lipogenesis, we overexpressed the chaperone glucose-regulated protein 78 (GRP78) in the livers of ob/ob mice using an adenoviral vector. GRP78 overexpression reduced ER stress markers and inhibited SREBP-1c cleavage and the expression of SREBP-1c and SREBP-2 target genes. Furthermore, hepatic triglyceride and cholesterol contents were reduced, and insulin sensitivity improved, in GRP78-injected mice. These metabolic improvements were likely mediated by restoration of IRS-2 expression and tyrosine phosphorylation. Interestingly, GRP78 overexpression also inhibited insulin-induced SREBP-1c cleavage in cultured primary hepatocytes. These findings demonstrate that GRP78 inhibits both insulin-dependent and ER stress-dependent SREBP-1c proteolytic cleavage and explain the role of ER stress in hepatic steatosis in obese rodents.
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Project description:ObjectiveThe rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD.DesignMice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies.ResultsAllelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar.ConclusionMboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.
| S-EPMC8040158 | biostudies-literature
Project description:Nonalcoholic fatty liver (NAFL) is increasingly recognized as one of the most common causes of chronic liver disease worldwide. Traditional Chinese medicine (TCM), as the alternative and complementary medicine, may provide some profound health benefit. "Jiang-Zhi" Granule (JZG) was composed based on TCM pathogenesis of NAFL: the retention of inner dampness, heat and blood stasis. This study investigated effects of JZG on liver X receptor-? (LXR?)/sterol regulatory element binding protein-1c (SREBP-1c) pathway in high-fat-diet-(HFD-)induced hepatic steatosis, as well as in free-fatty-acid-(FFA-)and T0901317-treated HepG2 cells. The results showed that JZG had an antisteatotic effect on HFD-fed rats. JZG decreased the activation of SREBP-1c through inhibiting LXR?-mediated SREBP-1c transcription, as well as through inhibiting the maturation of SREBP-1c independent of LXR?. These findings may provide molecular evidence for the use of JZG as a promising therapeutic option for NAFL and support us to continue JZG treatment in NAFL. For JZG treatment to be widely accepted, a randomized, double-blind, multicenter, placebo-controlled, phase III trial is ongoing.
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Project description:BackgroundNonalcoholic fatty liver disease is the most common chronic liver disease in the world, and is becoming increasingly prevalent. Saponins of sea cucumber (SSC) are proven to exhibit various biological activities. Therefore, the present study was undertaken to examine the effect of saponins extracted from sea cucumber (Pearsonothuria graeffei) on the preventive activity of fatty liver in rats.MethodsMale Wistar rats were randomly divided into five groups, including normal control group, fatty liver model group, SSC-treated group with SSC at levels of 0.01%, 0.03% and 0.05%. Model rats were established by administration with 1% orotic acid (OA). After the experiment period, serum total cholesterol (TC), triglyceride (TG), and hepatic lipid concentrations were determined. To search for a possible mechanism, we examined the changes of key enzymes and transcriptional factors involved in hepatic lipids biosynthesis, fatty acid beta-oxidation.ResultsBoth 0.03% and 0.05% SSC treatment alleviated hepatic steatosis and reduced serum TG and TC concentration significantly in OA fed rats. Hepatic lipogenic enzymes, such as fatty acid synthase (FAS), malic enzyme (ME), and glucose-6-phosphate dehydrogenase (G6PDH) activities were inhibited by SSC treatment. SSC also decreased the gene expression of FAS, ME, G6PDH and sterol-regulatory element binding protein (SREBP-1c). Otherwise, the rats feeding with SSC showed increased carnitine palmitoyl transferase (CPT) activity in the liver. Hepatic peroxisome proliferator-activated receptor (PPARalpha), together with its target gene CPT and acyl-CoA oxidase (ACO) mRNA expression were also upregulated by SSC.ConclusionsAccording to our study, the lipids-lowering effect of dietary SSC may be partly associated with the enhancement of beta-oxidation via PPARalpha activation. In addition, the inhibited SREBP-1c- mediated lipogenesis caused by SSC may also contribute to alleviating fatty liver.
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Project description:JAZF zinc finger 1 (JAZF1) is involved in glucose and lipid metabolisms. However, its role in aging- and nutrient-related hepatic steatosis is unclear. In the current study, we demonstrated that JAZF1 expression was markedly down-regulated in obesity-associated mice and nonalcoholic fatty liver disease (NAFLD) patients. During aging, JAZF1 expression was gradually down-regulated in both C57BL/6?J and JAZF1-Tg mice. In JAZF1-Tg mice, body fat content and hepatosteatosis were protected from HFD-induced steatosis, and accompanied by decreased lipogenesis gene expression. The inhibitory effects of hepatic steatosis in JAZF1-Tg mice, however, were disappeared during aging. In hepatocytes, over-expression of JAZF1 attenuated, while knockdown of JAZF1 enhanced the expression of lipogenesis genes. The over-expressing of JAZF1 in hepatocytes displayed the increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and decreased sterol regulatory element-binding protein 1c (SREBP-1c) expression. The roles of JAZF1 were partially attenuated by Compound C. Mechanistically, JAZF1 suppressed SREBP-1c expression through the inhibition of transcriptional activity of liver X receptor response elements (LXREs) in the SREBP-1c promoter. Data illustrate that JAZF1 may have a crucial role in the regulation of age and nutrient-associated hepatosteatosis through an AMPK/SREBP-1c-dependent mechanism.
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Project description:The SIRT1 deacetylase inhibits fat synthesis and stimulates fat oxidation in response to fasting, but the underlying mechanisms remain unclear. Here we report that SREBP-1c, a key lipogenic activator, is an in vivo target of SIRT1. SIRT1 interaction with SREBP-1c was increased during fasting and decreased upon feeding, and consistently, SREBP-1c acetylation levels were decreased during fasting in mouse liver. Acetylated SREBP-1c levels were also increased in HepG2 cells treated with insulin and glucose to mimic feeding conditions, and down-regulation of p300 by siRNA decreased the acetylation. Depletion of hepatic SIRT1 by adenoviral siRNA increased acetylation of SREBP-1c with increased lipogenic gene expression. Tandem mass spectrometry and mutagenesis studies revealed that SREBP-1c is acetylated by p300 at Lys-289 and Lys-309. Mechanistic studies using acetylation-defective mutants showed that SIRT1 deacetylates and inhibits SREBP-1c transactivation by decreasing its stability and its occupancy at the lipogenic genes. Remarkably, SREBP-1c acetylation levels were elevated in diet-induced obese mice, and hepatic overexpression of SIRT1 or treatment with resveratrol, a SIRT1 activator, daily for 1 week decreased acetylated SREBP-1c levels with beneficial functional outcomes. These results demonstrate an intriguing connection between elevated SREBP-1c acetylation and increased lipogenic gene expression, suggesting that abnormally elevated SREBP-1c acetylation increases SREBP-1c lipogenic activity in obese mice. Reducing acetylation of SREBP-1c by targeting SIRT1 may be useful for treating metabolic disorders, including fatty liver, obesity, and type II diabetes.
| S-EPMC2962496 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases with an increasing prevalence due to rising rates of obesity, metabolic syndrome and type II diabetes. Untreated NAFLD may progress to steatohepatitis (NASH) and ultimately liver cirrhosis. NAFLD is characterized by lipid accumulation, and when sufficient excess lipids are obtained, irreversible liver injury may follow. Perilipin 5 (PLIN5), a known lipid droplet coating protein and triglyceride metabolism regulator, is highly expressed in oxidatively modified tissues but it is still unclear how it affects NAFLD/NASH progress. We here studied how PLIN5 affects NAFLD development induced by a 30-week high-fat diet (HFD) administration in wild type and PLIN5 knock out (Plin5-/-) mice. The disruption of PLIN5 induced differences in lipid metabolism during HFD feeding and was associated with reduced hepatic fat accumulation. Surprisingly, Plin5-/- mice showed mitigated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, leading to minor hepatic damage. We conclude that PLIN5 is a pleiotropic regulator of hepatic homeostasis in NASH development. Targeting the PLIN5 expression appears critical for protecting the liver from inflammatory activation during chronic NAFLD.
| S-EPMC7348929 | biostudies-literature
Project description:Background and purposeLiver fibrosis is commonly associated with obesity and most obese patients develop hyperleptinaemia. The adipocytokine leptin has a unique role in the development of liver fibrosis. Activation of hepatic stellate cells (HSCs) is a key step in hepatic fibrogenesis and sterol regulatory element-binding protein-1c (SREBP-1c) can inhibit HSC activation. We have shown that leptin strongly inhibits SREBP-1c expression in rat HSCs. Hence, we aimed to clarify whether the ?-catenin pathway, the crucial negative regulator of adipocyte differentiation, mediates the effects of leptin on SREBP-1c expression in HSCs and in mouse liver fibrosis.Experimental approachHSCs were prepared from rats and mice. Gene expressions were analysed by real-time PCR, Western blot analysis, immunostaining and transient transfection assays.Key resultsLeptin increased ?-catenin protein but not mRNA levels in cultured HSCs. Leptin induced phosphorylation of glycogen synthase kinase-3? at Ser(9) and subsequent stabilization of ?-catenin protein was mediated, at least in part, by ERK and p38 MAPK pathways. The leptin-induced ?-catenin pathway reduced SREBP-1c expression and activity but did not affect protein levels of key regulators controlling SREBP-1c activity, and was not involved in leptin inhibition of liver X receptor ?. In a mouse model of liver injury, the ?-catenin pathway was shown to be involved in leptin-induced liver fibrosis.Conclusions and implicationsThe ?-catenin pathway contributes to leptin regulation of SREBP-1c expression in HSCs and leptin-induced liver fibrosis in mice. These results have potential implications for clarifying the mechanisms of liver fibrogenesis associated with elevated leptin levels.
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