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De novo lipogenesis drives both VLDL secretion and liver steatosis. Hepatic expression of the DNL enzymes depends on nutritional state. After food intake, increased glucose metabolism and elevated insulin signaling increase the activity of the transcription factors ChREBP and SREBP1, respectively. Under conditions of chronic energy excess and hyperinsulinemia prevalent in MAFLD, both lipogenic transcription factors and thus de novo lipogenesis are constantly active, which leads to elevated triglyceride synthesis from saturated fatty acids (SAFA) and monounsaturated fatty acids (MUFA). Stearoyl-CoA desaturase (SCD) catalyzes the generation of MUFA-CoA that are efficiently incorporated into triglycerides via diacylglycerol acyl transferase-2 (DGAT2) that directly associates with SCD. Of note, induction of SCD was observed to go along with increased VLDL secretion, and ChREBP promotes expression of proteins important for VLDL assembly (MTTP, TM6SF2). Together these findings indicate a strong link of DNL to VLDL secretion and dyslipidemia.
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Background
Non-alcoholic fatty liver disease, or as recently proposed ‘metabolic-associated fatty liver disease’ (MAFLD), is characterized by pathological accumulation of triglycerides and other lipids in hepatocytes. This common disease can progress from simple steatosis to steatohepatitis, and eventually end-stage liver diseases. MAFLD is closely...
Context in source publication
Citations
... The changes in lipid metabolism are pivotal in the development of NAFLD. Increased liver fat content in the pathogenesis of NAFLD is the result of the dysregulation of several pathways: uptake of free fatty acids, enhanced hepatic de novo lipogenesis (DNL), impaired beta-oxidation, and altered export of lipoproteins as components of very-low density lipoprotein (VLDL) [13]. As a result, dyslipidemia in patients with NAFLD is characterized by elevated serum triglycerides (TG) levels and decreased high-density lipoprotein cholesterol (HDL-C). ...
ABSTRACT
Type 2 diabetes mellitus (T2DM) and non-alcoholic liver disease (NAFLD)
shared a common feature, insulin resistance (IR), which is marked by achange in the lipoprotein fraction, namely increased triglycerides (TG) anddecreased high-density lipoprotein cholesterol (HDL-C) levels. Blood lipidsare routinely examined in T2DM patients; thus, our study aimed toinvestigate the performance of TG/HDL-C ratio values to identify hepaticsteatosis, the earliest manifestation of nonalcoholic fatty liver disease(NAFLD), in T2DM patients. One hundred adult T2DM patients over 30years old were recruited from the diabetes outpatient clinic at theDr. Soetomo General Academic Hospital from August to October 2023Data regarding sociodemographics, medication, glycosylated hemoglobin(HbA1c), lipid profiles, and FibroScan with controlled attenuation parameter(CAP) were collected from all participants. The group with hepatic steatosis
(CAP≥237 dB/m) had a higher body mass index (BMI), higher TG levels,and TG/HDL-C ratio values. The TG/HDL-C ratio was significantlycorrelated with CAP values. Hepatic steatosis can be identified using theTG/HDL-C ratio with a cut-off value of 2.83 (sensitivity:72.4%specificity:71.4%). An elevated TG/HDL-C ratio is associated with a higherisk (OR:6.562; p<0.05) of having hepatic steatosis. The TG/HDL-C ratio isa potential marker to predict NAFLD in T2DM patients.
Keywords:
Hepatic steatosis
Insulin resistance
NAFLD
TG/HDL-C ratio
Type 2 diabetes mellitus
... Decreased leptin levels have been shown to be associated with wasting and inflammation in TB patients [54]. Acute loss of adipocytes or body fat causes dyslipidemia and leads to lipid accumulation in various organs [55], and the accumulated lipid droplets can inhibit the phagocytic activation of macrophages [56,57]. In our previous study using the H37Rv (lab-adapted strain) infected FAT-ATTAC murine model, we demonstrated that FAB+ leads to increased lipid accumulation in the lungs and induces M2 polarization [9]. ...
The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence Mycobacterium tuberculosis (Mtb) burden, lung pathology, immune responses, and gene expression, with a focus on sex-specific dynamics. Utilizing a low-dose Mtb-HN878 clinical strain infection model, we employ transgenic FAT-ATTAC mice with modulable body fat to explore the impact of fat loss (via fat ablation) and fat gain (via a medium-fat diet, MFD). Firstly, our investigation unveils that Mtb infection triggers severe pulmonary pathology in males, marked by shifts in metabolic signaling involving heightened lipid hydrolysis and proinflammatory signaling driven by IL-6 and localized pro-inflammatory CD8+ cells. This stands in stark contrast to females on a control regular diet (RD). Secondly, our findings indicate that both fat loss and fat gain in males lead to significantly elevated (1.6-fold (p ≤ 0.01) and 1.7-fold (p ≤ 0.001), respectively) Mtb burden in the lungs compared to females during Mtb infection (where fat loss and gain did not alter Mtb load in the lungs). This upsurge is associated with impaired lung lipid metabolism and intensified mitochondrial oxidative phosphorylation-regulated activity in lung CD8+ cells during Mtb infection. Additionally, our research brings to light that females exhibit a more robust systemic IFNγ (p ≤ 0.001) response than males during Mtb infection. This heightened response may either prevent active disease or contribute to latency in females during Mtb infection. In summary, our comprehensive analysis of the interplay between body fat changes and sex bias in Mtb infection reveals that alterations in body fat critically impact pulmonary pathology in males. Specifically, these changes significantly reduce the levels of pulmonary CD8+ T-cells and increase the Mtb burden in the lungs compared to females. The reduction in CD8+ cells in males is linked to an increase in mitochondrial oxidative phosphorylation and a decrease in TNFα, which are essential for CD8+ cell activation.
... A genetic variant of apo-CIII leads to enhanced circulating apo-CIII in humans and is associated with NAFLD. 27,28 RARα suppresses hepatic apo-CIII expression through a pathway involving SHP and HNF4α, thereby reducing hepatic and plasma TG levels. Earlier studies have shown that RXR ligands have the opposite effect and enhance hepatic apo-CIII expression, either via RXR homodimers or RXR/PPARα, thereby promoting hypertriglyceridemia. Hypertriglyceridemia is a wellknown adverse effect of pharmacological ligands of RXR and a risk factor for cardiovascular disease. ...
... RXR ligands (such as 9cRA) on VLDL particle production and secretion by the liver. 16,27,28 In addition, vitamin A modulates the lipolysis of TGs inside the hepatocytes through a complex mechanism involving the adipose TG lipase (ATGL/PNPLA2), hormone-sensitive lipase, and PNPLA3 through the effects of PPARα and PPARα agonist. Liver diseases, especially those that lead to hepatic fibrosis, are often linked to disturbed vitamin A homeostasis. ...
... Development of steatosis reflects a chronic imbalance between, on the one hand, hepatic fatty acid uptake and triglyceride synthesis, and on the other, triglyceride metabolism and excretion. 2 Steatosis itself is not harmful and can usually be reversed by treating the underlying cause through lifestyle modifications and tighter glycaemic control. 3,4 However, if untreated, triglyceride deposition causes oxidative stress to hepatocytes, that eventually leads to chronic inflammation of the liver. ...
Background: The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis.
Methods: sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n = 156; male = 66, female = 90) and patients with liver tumours (n = 91; male = 58, female = 33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis.
Findings: Interleukin-4-secreting (IL-4+) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4+ iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4+ iNKT cells. sCD46 levels were elevatedin patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade.
Interpretation: sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis.
Funding: F.B. was supported by the Else Kröner Foundation (Award 2016_kolleg.14). G.G. was supported by the Bristol Myers Squibb Foundation for Immuno-Oncology (Award FA-19-009). N.S. was supported by a Wellcome Trust Fellowship (211113/A/18/Z). J.A.H. received funding from the European Union’s Horizon 2020 research and innovation programme (Award 860003). J.M.W. received funding from the Else Kröner Foundation (Award 2015_A10).
... The liver plays a major role in the distribution of lipids to the other organs. In the liver, fatty acids are converted to triglycerides and cholesterol esters, which are then secreted as VLDL [40]. Imbalances in lipid metabolism in the liver can induce steatosis or the accumulation of triglycerides in hepatocytes [41]. ...
Long-term hepatic damage is associated with human morbidity and mortality owing to numerous pathogenic factors. A variety of studies have focused on improving liver health using natural products and herbal medicines. We aimed to investigate the effect of enzyme-treated Zizania latifolia ethanol extract (ETZL), which increases the content of tricin via enzymatic hydrolysis, for 8 weeks on liver-related outcomes, lipid metabolism, antioxidant activity, and fatigue compared to a placebo. Healthy Korean adult males aged 19–60 years were randomized into ETZL treatment and placebo groups, and alcohol consumption was 24.96 and 28.64 units/week, respectively. Alanine transaminase, a blood marker associated with liver cell injury, significantly decreased after 8 weeks compared to the baseline in the ETZL treatment group (p = 0.004). After 8 weeks, the treatment group showed significant changes in the levels of high-density lipoprotein and hepatic steatosis index compared to the baseline (p = 0.028 and p = 0.004, respectively). ETZL treatment tended to reduce antioxidant-activity-related factors, total antioxidant status, and malondialdehyde, but there was no significant difference. In the multidimensional fatigue scale, ETZL treatment showed a significant reduction in general fatigue and total-fatigue-related values after 8 weeks compared to the baseline (p = 0.012 and p = 0.032, respectively). Taken together, the 8-week treatment of enzyme-treated Zizania latifolia ethanol extract demonstrated positive effects on liver-related outcomes, lipid metabolism, and mental fatigue without adverse effects on safety-related parameters.
... With respect to etiologies underlying end-stage liver disease requiring transplantation, elevated TMAO levels in polycystic liver disease are likely due to the coinciding impaired kidney function, thereby compromising renal TMAO excretion [14]. MASLD has a strong association with dysglycemia and dyslipidemia [52,53]. In line with current findings, plasma TMAO was reported to be increased in PREVEND participants with an elevated fatty liver index, as a proxy of MASLD [25]. ...
Liver transplant recipients (LTRs) have lower long-term survival rates compared with the general population. This underscores the necessity for developing biomarkers to assess post-trans-plantation mortality. Here we compared plasma trimethylamine-N-oxide (TMAO) levels with those in the general population, investigated its determinants, and interrogated its association with all-cause mortality in stable LTRs. Plasma TMAO was measured in 367 stable LTRs from the Trans-plantLines cohort (NCT03272841) and in 4837 participants from the population-based PREVEND cohort. TMAO levels were 35% higher in LTRs compared with PREVEND participants (4.3 vs. 3.2 µmol/L, p < 0.001). Specifically, TMAO was elevated in LTRs with metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and polycystic liver disease as underlying etiology (p < 0.001 for each). Among LTRs, TMAO levels were independently associated with eGFR (std. β = −0.43, p < 0.001) and iron supplementation (std. β = 0.13, p = 0.008), and were associated with mortality (29 deaths during 8.6 years follow-up; log-rank test p = 0.017; hazard ratio of highest vs. lowest tertile 4.14, p = 0.007). In conclusion, plasma TMAO is likely elevated in stable LTRs, with impaired eGFR and iron supplementation as potential contributory factors. Our preliminary findings raise the possibility that plasma TMAO could contribute to increased mortality risk in such patients, but this need to be validated through a series of rigorous and methodical studies.
... In the present study, both A. muciniphila and VSL#3 alleviated liver damage, improved liver function ( Figure 1D), and reduced hepatic inflammation and lipid accumulation (Figure 2A-F). The common features of NAFLD-related dyslipidemia are hypertriglyceridemia, increased LDL concentration, and decreased HDL concentration, which is consistent with the lipid profile of MCD in the present study [35]. Despite the lack of a significant difference in serum TG between groups MCD_A and MCD_V ( Figure 1E), the level of LDL the amount of hepatic fat in the liver was shown to be reduced more by A. muciniphila than by VSL#3, using oil red O staining ( Figure 2C). ...
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition worldwide. Numerous studies conducted recently have demonstrated a connection between the dysbiosis of the development of NAFLD and gut microbiota. Rebuilding a healthy gut ecology has been proposed as a strategy involving the use of probiotics. The purpose of this work is to investigate and compare the function of probiotics Akkermansia muciniphila (A. muciniphila) and VSL#3 in NAFLD mice. Rodent NAFLD was modeled using a methionine choline-deficient diet (MCD) with/without oral probiotic delivery. Subsequently, qPCR, histological staining, and liver function tests were conducted. Mass spectrometry-based analysis and 16S rDNA gene sequencing were used to investigate the liver metabolome and gut microbiota. We found that while both A. muciniphila and VSL#3 reduced hepatic fat content, A. muciniphila outperformed VSL#3. Furthermore, probiotic treatment restored the β diversity of the gut flora and A. muciniphila decreased the abundance of pathogenic bacteria such as Ileibacterium valens. These probiotics altered the metabolism in MCD mice, especially the glycerophospholipid metabolism. In conclusion, our findings distinguished the role of A. muciniphila and VSL#3 in NAFLD and indicated that oral-gavage probiotics remodel gut microbiota and improve metabolism, raising the possibility of using probiotics in the cure of NAFLD.
... Aliphatic acid synthesis and metabolic pathways are crucial players in the occurrence and advancement of hepatic fibrosis. As a major organ for aliphatic acid synthesis and metabolism, the liver has the ability to synthesize, break down, and metabolize aliphatic acids (Heeren and Scheja, 2021). In certain pathological states, such as obesity, hyperlipidemia, and hepatic fibrosis, the liver is susceptible to excessive lipid accretion (Ran et al., 2023). ...
... In certain pathological states, such as obesity, hyperlipidemia, and hepatic fibrosis, the liver is susceptible to excessive lipid accretion (Ran et al., 2023). Adipocyte proliferation, white blood cell infiltration, and cytokine release can induce the deposition and accretion of lipids in hepatocytes, exacerbating the occurrence and progression of hepatic fibrosis (Suganami et al., 2012;van der Windt et al., 2018;Heeren and Scheja, 2021). Transforming growth factor-beta (TGF-β), a critical mediator in hepatic fibrosis, is able to stimulate hepatic stellate cell diffusion as well as collagen deposition. ...
Background and purpose
As a traditional Chinese medicine formula, Yangyinghuoxue Decoction (YYHXD) is used clinically for therapy of hepatic fibrosis. The pharmacological profile of YYHXD comprises multiple components acting on many targets and pathways, but the pharmacological mechanisms underlying its efficacy have not been thoroughly elucidated. This study aimed at probing the pharmacological mechanisms of YYHXD in the treatment of hepatic fibrosis.
Methods
YYHXD aqueous extract was prepared and quality control using HPLC-MS fingerprint analysis was performed. A CCl4-induced rat model of hepatic fibrosis was established, and animals were randomly assigned to six groups: control, low-dose YYHXD (L-YYHXD), medium-dose YYHXD (M-YYHXD), high-dose YYHXD (H-YYHXD), CCl4 model, and colchicine group. Rats in the treatment groups received daily oral administration of YYHXD (5, 10, or 20 g/kg) or colchicine (0.2 mg/kg) for 6 weeks, while the control and model groups received distilled water. Histological analysis, including hematoxylin and eosin (HE) and Masson’s trichrome staining, was performed to evaluate hepatic fibrosis. Serum biochemical markers, such as AST, ALT, HA, and LN, were measured. Inflammatory cytokines (IL-6 and TNF-α) and oxidative stress indicators (SOD, GSH-Px, and MDA) in hepatic tissue were also assessed. Additionally, transcriptomic analysis using RNA-sequencing was conducted to identify differentially expressed genes (DEGs) between the control, CCl4 model, and H-YYHXD groups. Bioinformatics analysis, including differential expression analysis, protein-protein interaction analysis, and functional enrichment analysis, were performed to probe the pharmacological mechanisms of YYHXD. The regulatory effects of YYHXD on fatty acid metabolism and biosynthesis were further confirmed by Oil Red O staining, enzyme activity assays, qPCR, and Western blotting. Western blotting and immunofluorescence staining also validated the involvement of the AMPK signaling pathway in the occurrence and progression of hepatic fibrosis.
Results
HE and Masson’s trichrome staining revealed reduced collagen deposition and improved liver architecture in YYHXD groups compared to the CCl4 model group. Serum biochemical markers, including AST, ALT, HA, and LN, were significantly improved in the YYHXD-treated groups compared to the CCl4 model group. The levels of inflammatory cytokines (IL-6 and TNF-α) and oxidative stress indicators (decreased SOD and GSH-Px, increased MDA) in hepatic tissue were significantly ameliorated by YYHXD treatment compared to the CCl4 model group. Moreover, 96 genes implicated in YYHXD therapy of hepatic fibrosis were screened from the transcriptomic data, which were principally enriched in biological pathways such as fatty acid metabolism and biosynthesis, and the AMPK signaling pathway. Oil Red O staining showed reduced hepatic lipid accumulation by YYHXD in a dose-dependent manner, along with decreased serum TG, TC, and LDL-C levels. Additionally, qPCR and Western blot analyses demonstrated upregulated mRNA and protein expression of key enzymes involved in fatty acid metabolism and biosynthesis, Fasn and Fads2, modulated by YYHXD. YYHXD also dose-dependently enhanced phosphorylation of AMPK as evidenced by Western blotting and immunofluorescence assays.
Conclusion
YYHXD ameliorated CCl4-induced hepatic fibrosis in rats through pharmacological mechanisms that involved manifold targets and pathways, including aliphatic acid synthesis and metabolism pathways and the AMPK signaling pathway. This study provided a reference and basis for further research and clinical utilization of YYHXD.
... Hepatocytes digest and endocytose these remnants, allowing the re-secretion of smaller lipids as VLDLs, subsequently released into the bloodstream. The occurrence of NASH is a result of the synthesis or import of lipids in hepatocytes surpassing the export or degradation [35][36][37] . Furthermore, these small lipids, including VLDL, may be absorbed by macrophage scavenger receptors without limit, exhibit cytotoxic and pro-in ammatory properties within macrophage and thereby promote the transformation of macrophage into foam cells 13,38,39 . ...
Background
Few studies have explored the relationship between remnant cholesterol (RC) and liver fibrosis in nonalcoholic fatty liver disease (NAFLD). Therefore, this study aims to explore the association between RC levels and liver fibrosis in both biopsy-proven NAFLD population and Sprague-Dawley (SD) rats.
Methods
This current study included 280 participants and 15 SD rats. For NAFLD population, all participants underwent liver biopsy and blood tests. Logistic regression analysis was used to evaluate the association between RC and liver fibrosis and the diagnostic capability of RC was assessed by receiver operating characteristic (ROC) curve analysis. For NAFLD rats, pathological and hematological analysis were used to study the association between RC and liver fibrosis.
Results
In NAFLD population, RC remain significantly associated with liver fibrosis after confounding factors were adjusted (OR:1.21, 95% confidence interval [CI]: 1.09–1.49, p < 0.001). In addition, RC and liver fibrosis were still significantly associated with liver fibrosis when triglycerides (TG) levels were less than 1.7 mmol/L (OR: 1.13, 95% CI: 1.03–1.56, p = 0.006), low-density lipoprotein cholesterol (LDL-C) levels were less than 3.4 mmol/L (OR: 1.18, 95% CI: 1.08–1.43, p < 0.001), or HDL-C (high-density lipoprotein cholesterol) levels were more than 1.0 mmol/L (OR: 1.20, 95% CI: 1.08–1.47, p < 0.001). In the NAFLD rats, rats with fibrosis exhibited higher RC levels (p < 0.001) and elevated RC was significantly correlated with liver fibrosis (r = 0.819, p < 0.001).
Conclusion
Higher RC level is significantly correlated with liver fibrosis in the NAFLD population and rats.
... This could be owing to the occurrence of liver damage. Possible causes include malfunctions in the systems that pair triglycerides with the proper apoprotein to make the transport molecule (lipoprotein) [82]. Albino rats exposed to CCl4 had their TC, TG, LDL, and HDL levels restored to normal range using treatment with MO leaf aqueous extract, greenly synthesized ZnO-NPs, and ZnO-NPs, suggesting that these NPs may facilitate oxidative reactions to preserve blood hemostasis. ...
Hepatotoxin carbon tetrachloride (CCl4) causes liver injury. This research aims to create
ZnO-NPs using green synthesis from Moringa oleifera (MO) leaves aqueous extract, and
chemically prepared and confirming the synthesis by specialized equipment analysis.
The sizes formed of ZnO-NPs were 80 and 55 nm for chemical and green methods,
respectively. In addition, to study their ability to protect Wistar Albino male rats against
oxidative stress exposed to carbon tetrachloride. MO leaf aqueous extract, green
synthesized ZnO-NPs, and ZnO-NPs prepared chemically at 100 and 200 mg/kg BW per
day were investigated for their hepatoprotective effects on liver enzyme biomarkers,
renal biomarkers, antioxidant enzymes, lipid peroxidation, hematological parameters,
and histopathological changes. Compared to the control group, all liver and kidney
indicators were considerably elevated after the CCl4 injection. However, the activity of
antioxidant enzymes in the liver was significantly reduced after the CCl4 injection. These
outcomes indicate that MO leaf aqueous extract, greenly synthesized ZnO-NPs, and ZnONPs
chemically prepared can restore normal liver and kidney function and activity, as
well as hematological and antioxidant enzymes. The highest impact on enhancing the
hepatoprotective effect was recorded for rats that received green synthesized ZnO-NPs.
The increased drug delivery mechanism of green synthesized ZnO-NPs resulted in a
higher protective effect than that of MO leaf aqueous extract.
