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OXPHOS-Mediated Induction of NAD+ Promotes Complete Oxidation of Fatty Acids and Interdicts Non-Alcoholic Fatty Liver Disease.

ABSTRACT: OXPHOS is believed to play an important role in non-alcoholic fatty liver disease (NAFLD), however, precise mechanisms whereby OXPHOS influences lipid homeostasis are incompletely understood. We previously reported that ectopic expression of LRPPRC, a protein that increases cristae density and OXPHOS, promoted fatty acid oxidation in cultured primary hepatocytes. To determine the biological significance of that observation and define underlying mechanisms, we have ectopically expressed LRPPRC in mouse liver in the setting of NAFLD. Interestingly, ectopic expression of LRPPRC in mouse liver completely interdicted NAFLD, including inflammation. Consistent with mitigation of NAFLD, two markers of hepatic insulin resistance--ROS and PKCε activity--were both modestly reduced. As reported by others, improvement of NAFLD was associated with improved whole-body insulin sensitivity. Regarding hepatic lipid homeostasis, the ratio of NAD+ to NADH was dramatically increased in mouse liver replete with LRPPRC. Pharmacological activators and inhibitors of the cellular respiration respectively increased and decreased the [NAD+]/[NADH] ratio, indicating respiration-mediated control of the [NAD+]/[NADH] ratio. Supporting a prominent role for NAD+, increasing the concentration of NAD+ stimulated complete oxidation of fatty acids. Importantly, NAD+ rescued impaired fatty acid oxidation in hepatocytes deficient for either OXPHOS or SIRT3. These data are consistent with a model whereby augmented hepatic OXPHOS increases NAD+, which in turn promotes complete oxidation of fatty acids and protects against NAFLD.

SUBMITTER: Akie TE

PROVIDER: S-EPMC4416931 | biostudies-literature |

REPOSITORIES: biostudies-literature

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GBA3 promotes fatty acid oxidation and alleviates non-alcoholic fatty liver by increasing CPT2 transcription.

Project description:BackgroundExcessive lipids accumulation and hepatocytes death are prominent characteristics of non-alcoholic fatty liver disease (NAFLD). Nonetheless, the precise pathophysiological mechanisms are not fully elucidated.MethodsHepG2 cells stimulated with palmitic acids and rats fed with high-fat diet were used as models for NAFLD. The impact of Glucosylceramidase Beta 3 (GBA3) on fatty acid oxidation (FAO) was assessed using Seahorse metabolic analyzer. Lipid content was measured both in vitro and in vivo. To evaluate NAFLD progression, histological analysis was performed along with measurements of inflammatory factors and liver enzyme levels. Western blot and immunohistochemistry were employed to examine the activity levels of necroptosis. Flow cytometry and reactive oxygen species (ROS) staining were utilized to assess levels of oxidative stress.ResultsGBA3 promoted FAO and enhanced the mitochondrial membrane potential without affecting glycolysis. These reduced the lipid accumulation. Rats supplemented with GBA3 exhibited lower levels of inflammatory factors and liver enzymes, resulting in a slower progression of NAFLD. GBA3 overexpression reduced ROS and the ratio of cell apoptosis. Phosphorylation level was reduced in the essential mediator, MLKL, implicated in necroptosis. Mechanistically, as a transcriptional coactivator, GBA3 promoted the expression of Carnitine Palmitoyltransferase 2 (CPT2), which resulted in enhanced FAO.ConclusionsIncreased FAO resulting from GBA3 reduced oxidative stress and the production of ROS, thereby inhibiting necroptosis and delaying the progression of NAFLD. Our research offers novel insights into the potential therapeutic applications of GBA3 and FAO in the management and treatment of NAFLD.

| S-EPMC10968678 | biostudies-literature

Bile Acids and Dysbiosis in Non-Alcoholic Fatty Liver Disease.

Project description:Background & aimsNon-alcoholic fatty liver disease (NAFLD) is characterized by dysbiosis. The bidirectional effects between intestinal microbiota (IM) and bile acids (BA) suggest that dysbiosis may be accompanied by an altered bile acid (BA) homeostasis, which in turn can contribute to the metabolic dysregulation seen in NAFLD. This study sought to examine BA homeostasis in patients with NAFLD and to relate that with IM data.MethodsThis was a prospective, cross-sectional study of adults with biopsy-confirmed NAFLD (non-alcoholic fatty liver: NAFL or non-alcoholic steatohepatitis: NASH) and healthy controls (HC). Clinical and laboratory data, stool samples and 7-day food records were collected. Fecal BA profiles, serum markers of BA synthesis 7-alpha-hydroxy-4-cholesten-3-one (C4) and intestinal BA signalling, as well as IM composition were assessed.Results53 subjects were included: 25 HC, 12 NAFL and 16 NASH. Levels of total fecal BA, cholic acid (CA), chenodeoxycholic acid (CDCA) and BA synthesis were higher in patients with NASH compared to HC (p<0.05 for all comparisons). The primary to secondary BA ratio was higher in NASH compared to HC (p = 0.004), but ratio of conjugated to unconjugated BAs was not different between the groups. Bacteroidetes and Clostridium leptum counts were decreased in in a subset of 16 patients with NASH compared to 25 HC, after adjusting for body mass index and weight-adjusted calorie intake (p = 0.028 and p = 0.030, respectively). C. leptum was positively correlated with fecal unconjugated lithocholic acid (LCA) (r = 0.526, p = 0.003) and inversely with unconjugated CA (r = -0.669, p<0.0001) and unconjugated CDCA (r = - 0.630, p<0.0001). FGF19 levels were not different between the groups (p = 0.114).ConclusionsIn adults with NAFLD, dysbiosis is associated with altered BA homeostasis, which renders them at increased risk of hepatic injury.

| S-EPMC4874546 | biostudies-literature

Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease [liver]

Project description:Scope: Consumption of industrial trans fatty acids unfavourably alters plasma cholesterol and has been linked to NAFLD. However, the mechanisms underlying these deleterious effects of trans fatty acids are unclear. Here, we aim to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods & Results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells showed that elaidate but not oleate or palmitate induced expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate was mediated by increased SREBP2 and dependent on SCAP, yet independent of LXR and UBXD8. Elaidate decreased intracellular free cholesterol levels and repressed the anti-cholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increased the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, ALT activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. Conclusion: Elaidate induces cholesterogenesis in vitro via activation of the SCAP-SREBP axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

2019-08-27 | GSE136271 | GEO

Free Fatty Acids Differentially Downregulate Chemokines in Liver Sinusoidal Endothelial Cells: Insights into Non-Alcoholic Fatty Liver Disease.

Project description:Non-alcoholic fatty liver disease is a prevalent problem throughout the western world. Liver sinusoidal endothelial cells (LSEC) have been shown to play important roles in liver injury and repair, but their role in the underlying pathogenetic mechanisms of non-alcoholic fatty liver disease remains undefined. Here, we evaluated the effects of steatosis on LSEC gene expression in a murine model of non-alcoholic fatty liver disease and an immortalized LSEC line. Using microarray we identified distinct gene expression profiles following exposure to free fatty acids. Gene pathway analysis showed a number of differentially expressed genes including those involved in lipid metabolism and signaling and inflammation. Interestingly, in contrast to hepatocytes, fatty acids led to decreased expression of pro-inflammatory chemokines including CCL2 (MCP-1), CXCL10 and CXCL16 in both primary and LSEC cell lines. Chemokine downregulation translated into a significant inhibition of monocyte migration and LSECs isolated from steatotic livers demonstrated a similar shift towards an anti-inflammatory phenotype. Overall, these pathways may represent a compensatory mechanism to reverse the liver damage associated with non-alcoholic fatty liver disease.

| S-EPMC4959750 | biostudies-literature

Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing.

Project description:Background and purposeAgeing is an important risk factor of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD(+) ), a ubiquitous coenzyme, links ageing with NAFLD.Experimental approachHepatic concentrations of NAD(+) , protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD(+) biosynthesis, were compared in middle-aged and aged mice or patients. The influences of NAD(+) decline on the steatosis and steatohepatitis were evaluated in wild-type and H247A dominant-negative, enzymically-inactive NAMPT transgenic mice (DN-NAMPT) given normal or high-fat diet (HFD).Key resultsHepatic NAD(+) level decreased in aged mice and humans. NAMPT-controlled NAD(+) salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle-age DN-NAMPT mice displayed systemic NAD(+) reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro-inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α-SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD(+) precursor, completely corrected these NAFLD phenotypes induced by NAD(+) deficiency alone or HFD, whereas adenovirus-mediated SIRT1 overexpression only partially rescued these phenotypes.Conclusions and implicationsThese results provide the first evidence that ageing-associated NAD(+) deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD(+) substrates may be a promising therapeutic strategy to prevent and treat NAFLD.

| S-EPMC4945761 | biostudies-literature

Silibinin Restores NAD⁺ Levels and Induces the SIRT1/AMPK Pathway in Non-Alcoholic Fatty Liver.

Project description:Nicotinamide adenine dinucleotide (NAD⁺) homeostasis is emerging as a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and is tightly linked to the SIRT1/5'-AMP-activated protein kinase (AMPK) pathway. Silibinin, the main component of silymarin, has been proposed as a nutraceutical for the treatment of NAFLD. In this study, we aimed to identify whether silibinin may influence the NAD⁺/SIRT1 axis. To this end, C57BL/6 mice were fed a high fat diet (HFD) for 16 weeks, and were treated with silibinin or vehicle during the last 8 weeks. HepG2 cells were treated with 0.25 mM palmitate for 24 h with silibinin 25 µM or vehicle. HFD and palmitate administration led to oxidative stress, poly-(ADP-ribose)-polymerase (PARP) activation, NAD⁺ consumption, and lower SIRT1 activity. In mice fed the HFD, and in HepG2 treated with palmitate, we consistently observed lower levels of phospho-AMPKThr172 and phospho-acetyl-CoA carboxylaseSer79 and higher levels of nuclear sterol regulatory element-binding protein 1 activity, indicating de novo lipogenesis. Treatment of mice and HepG2 with silibinin abolished oxidative stress, and inhibited PARP activation thus restoring the NAD⁺ pool. In agreement with preserved NAD⁺ levels, SIRT1 activity and AMPK phosphorylation returned to control levels in mice and HepG2. Our results further indicate silibinin as a promising molecule for the treatment of NAFLD.

| S-EPMC5691703 | biostudies-literature

Industrial Trans Fatty Acids Stimulate SREBP2-Mediated Cholesterogenesis and Promote Non-Alcoholic Fatty Liver Disease.

Project description:ScopeThe mechanisms underlying the deleterious effects of trans fatty acids on plasma cholesterol and non-alcoholic fatty liver disease (NAFLD) are unclear. Here, the aim is to investigate the molecular mechanisms of action of industrial trans fatty acids.Methods and resultsHepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated, or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells shows that elaidate but not oleate or palmitate induces expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate is mediated by increased sterol regulatory element-binding protein 2 (SREBP2) activity and is dependent on SREBP cleavage-activating protein (SCAP), yet independent of liver-X receptor and ubiquitin regulatory X domain-containing protein 8. Elaidate decreases intracellular free cholesterol levels and represses the anticholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increases the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, alanine aminotransferase activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets.ConclusionElaidate induces cholesterogenesis in vitro by activating the SCAP-SREBP2 axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

| S-EPMC6790681 | biostudies-literature

Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation.

Project description:Nonalcoholic fatty liver disease (NAFLD) is considered the next major health epidemic with an estimated 25% worldwide prevalence. No drugs have yet been approved and NAFLD remains a major unmet need. Here, we identify MCJ (Methylation-Controlled J protein) as a target for non-alcoholic steatohepatitis (NASH), an advanced phase of NAFLD. MCJ is an endogenous negative regulator of the respiratory chain Complex I that acts to restrain mitochondrial respiration. We show that therapeutic targeting of MCJ in the liver with nanoparticle- and GalNAc-formulated siRNA efficiently reduces liver lipid accumulation and fibrosis in multiple NASH mouse models. Decreasing MCJ expression enhances the capacity of hepatocytes to mediate β-oxidation of fatty acids and minimizes lipid accumulation, which results in reduced hepatocyte damage and fibrosis. Moreover, MCJ levels in the liver of NAFLD patients are elevated relative to healthy subjects. Thus, inhibition of MCJ emerges as an alternative approach to treat NAFLD.

| S-EPMC7334216 | biostudies-literature

Industrial trans fatty acids stimulate SREBP2-mediated cholesterogenesis and promote non-alcoholic fatty liver disease

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-08-27 | GSE136354 | GEO

Dietary fatty acid oxidation is decreased in non-alcoholic fatty liver disease: A palmitate breath test study.

Project description:Background & aimHepatic fat excess in non-alcoholic fatty liver disease (NAFLD) reflects an imbalance between fat accumulation and disposal. Conflicting data exist for the role of fatty acid oxidation (FAO), one of the disposal pathways, and have mostly come from the studies delivering fatty acids (FAs) intravenously. Whether FAO of orally provided FAs is affected in NAFLD is unknown.MethodsWe performed a breath test study to measure FAO in subjects with NAFLD and healthy controls. Subjects ingested [1-13 C] palmitic acid (PA, 10 mg/kg) in a liquid meal and the rate of 13 CO2 appearance in expired air was measured over 6 hours by a BreathID device (Exalenz) to obtain the cumulative percent dose recovered (CPDR), the total amount of ingested 13 C recovered. CPDR was corrected by the results of a [1-13 C] acetate breath test, performed 1-4 weeks later, to calculate the rate of PA ?-oxidation.ResultsPalmitic acid oxidation was 27% lower in 43 subjects with NAFLD compared to 11 controls (CPDR 9.5 ± 2.4% vs 13.1 ± 3.7%, P = .0001) and this persisted after correcting for acetate (29.3 ± 10.5 vs 36.6 ± 13.9, P = .03). The decrease in FAO was not because of the delayed transit as the time to peak 13 C detection did not differ between groups (4.9 ± 1.2 hours vs 4.7 ± 0.8 hours, P = .7). Rates of PA oxidation were not correlated with obesity, hepatic or adipose insulin resistance, alanine aminotransferase, liver fat content and NAFLD histology.ConclusionFatty acid oxidation of orally delivered FA is decreased in NAFLD compared to healthy controls, likely reflecting decreased ?-oxidation. The use of a breath test offers non-invasive dynamic assessment of FAO.

| S-EPMC7056545 | biostudies-literature

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