Hepatic Fat Accumulation Research Articles

Improvement of hepatic innate immunity in chemically-injured livers to develop hepatocarcinoma by a serine type-protease inhibitors enriched extract from Chenopodium quinoa.

Food ingredients have critical effects on the maturation and development of the immune system, which innate - lymphoid (ILCs) and myeloid - cells play key roles as important regulators of energy storage and hepatic fat accumulation. Therefore, the objective of this study is to define potential links between a dietary immunonutritional induction of the selective functional differentiation of monocytes-derived macrophages, ILCs and lipid homeostasis in hepatocarcinoma (HCC)-developing mice. Hepatic chemically injured (diethylnitrosamine/thiacetamide) Rag2-/- and Rag2-/-Il2-/- mice were administered with serine-type protease inhibitors (SETIs) obtained from Chenopodium quinoa. Early HCC-driven immunometabolic imbalances (infiltrated macrophages, glucose homeostasis, hepatic lipid profile, ILCs expansion, inflammatory conditions, microbiota) in animals put under a high-fat diet for 2 weeks were assessed. It was also approached the potential of SETIs to cause functional adaptations of the bioenergetics of human macrophage-like cells (hMLCs) in vitro conditioning their capacity to accumulate fat. It is showed that Rag2-/-Il2-/- mice, lacking ILCs, are resistant to the SETIs-induced hepatic macrophages (CD68+F4/80+) activation. Feeding SETIs to Rag2-/- mice, carrying ILCs, promoted the expansion towards ILC3s (CD117+Nkp46+CD56+) and reduced that of ILC2s (CD117+KLRG1+) into livers. In vitro studies demonstrate that hMLCs, challenged to SETIs, develop a similar phenotype of that found in mice and bioenergetic adaptations leading to increased lipolysis. It is concluded that SETIs promote liver macrophage activation and ILCs adaptations to ameliorate HCC-driven immunometabolic imbalances.

Evaluation of the role of some non-enzymatic antioxidants among Iraqi patients with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), characterized by hepatic fat accumulation in individuals consuming little or no alcohol, has become highly prevalent globally. Oxidative stress plays a central role in instigating inflammation and cell death pathways driving NAFLD progression. This case-control study aimed to elucidate the association between circulating levels of the pivotal non-enzymatic antioxidants - coenzyme Q10 and vitamins E and C - and liver injury parameters among 60 Iraqi NAFLD patients versus 30 healthy controls. NAFLD diagnosis entailed over 5% hepatic steatosis on ultrasound excluding other etiologies. Patients spanned three age groups: 20-29, 30-39, and 40-49. Substantially diminished antioxidant levels concurrent with elevated alkaline phosphatase enzyme were unveiled in NAFLD patients relative to controls (all p < 0.001). Age-based analysis reinforced widespread antioxidant depletion and liver enzyme augmentation across NAFLD patients. Significant correlations also emerged between antioxidants and liver parameters. Our novel observations confirm an antioxidant inadequacy likely perpetuating pathogenic oxidative reactions in NAFLD. Restoring such deficits through lifestyle or therapeutic interventions may confer preventative and disease-modifying value.

Protocatechuic acid alleviates TMAO-aggravated atherosclerosis via mitigating inflammation, regulating lipid metabolism, and reshaping gut microbiota.

Trimethylamine-N-oxide (TMAO) is a risk factor for atherosclerosis. As a natural phenolic acid, protocatechuic acid (PCA) is abundant in various plant foods. The present study investigated the effect of PCA on TMAO-aggravated atherosclerosis in ApoE-/- mice. The mice were randomly divided into five groups and fed one of the following five diets for 12 weeks: namely a low-fat diet (LFD), a western diet (WD), a WD + 0.2% TMAO diet (WDT), a WDT + 0.5% PCA diet (WDT + LPCA), and a WDT + 1.0% PCA diet (WDT + HPCA). Results demonstrated that dietary TMAO exacerbated the development of atherosclerosis by eliciting inflammation and disturbing lipid metabolism. The diet with PCA at 1% reduced TMAO-induced aortic plaque by 30% and decreased the levels of plasma pro-inflammatory cytokines. PCA also improved lipid metabolism by up-regulating the hepatic gene expression of peroxisome proliferator-activated receptor alpha (PPARα). In addition, PCA supplementation enhanced fecal excretion of fatty acids and decreased hepatic fat accumulation. PCA supplementation favorably modulated gut microbiota by increasing the α-diversity with an increase in the abundance of beneficial genera (Rikenella, Turicibacter, Clostridium_sensu_stricto and Bifidobacterium) and a decrease in the abundance of the harmful Helicobacter genus. In summary, PCA could alleviate the TMAO-exacerbated atherosclerosis and inflammation, improve the lipid metabolism, and modulate gut microbiota.

Can dysmetabolic comorbidities carry hepatic fat accumulation in patients with inflammatory bowel diseases?

Can dysmetabolic comorbidities carry hepatic fat accumulation in patients with inflammatory bowel diseases?

Treatment with a new barbituric acid derivative suppresses diet-induced metabolic dysfunction and non-alcoholic fatty liver disease in mice

IntroductionNonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, often accompanied by obesity, diabetes, and increased risks of depression and anxiety. Currently, there are no FDA-approved drugs to treat NAFLD and its related systemic symptoms. Previously, we identified a new barbituric acid derivative (BA-5) that expressed effectiveness against fibrosis and drug-resistant hepatocellular carcinoma. AimsThis study investigated the potential of BA-5 against high-fat diet (HFD)-induced NAFLD and mood disorders in mice. Main methodsSix-weeks-old male C57BL/6 mice were fed with a 45 % HFD for 8 weeks to induce NAFLD and associated metabolic disorders. Mice were treated with a BA-5 and the therapeutic effects and the underlying molecular mechanisms were investigated. Key findingsAdministration of BA-5 significantly reduced serum levels of alanine aminotransferase (ALT), low-density lipoprotein (LDL), fatty acids (FA), and triglycerides (TG) in HFD-fed mice. BA-5 treatment decreased expressions of hepatic lipogenesis-related markers (acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and ATP-citrate lyase (ACLY)), increased fatty acid oxidation markers (carnitine palmitoyltransferase 1A (CPT1A) and acyl-CoA oxidase 1 (ACOX1)), and attenuated hepatic fat accumulation in HFD-fed mice. Moreover, HFD-induced adipocyte size enlargement and activation of lipolysis markers such as phosphorylated (p)-hormone-sensitive lipase (HSL) 565, p-HSL 660, and perilipin were inhibited in BA-5-treated mice. Notably, HFD-induced anxiety- and depression-like behaviors significantly improved in the BA-5 treated group through enhanced anti-inflammatory responses in the hippocampus. SignificanceThis study provides new insights into clinical therapeutic strategies of barbituric acid derivatives for HFD-induced NAFLD and associated mood disturbances.

HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor.

Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits. This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet (HFD) and explored the involvement of endoplasmic reticulum (ER) stress. Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine (3 mg/kg/day) and the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 1 and 0.5 g/kg/day) for 8 days. Changes in body weight, food intake, and plasma lipids were assessed. Hepatic fat accumulation was evaluated using oil red O staining. Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), and proopiomelanocortin (POMC) in the hypothalamus or liver. Compared to olanzapine alone, olanzapine+HFD induced greater weight gain, increased hyperlipidemia, and enhanced hepatic fat accumulation (P<0.05). Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects (P<0.05). Further mechanistic investigations revealed that olanzapine alone activated ER stress, upregulated NLRP3 expression in the hypothalamus and liver, and downregulated hypothalamic POMC expression. The HFD exacerbated these effects by 50%-100%. Moreover, co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress, NLRP3, and POMC expression in the hypothalamus and liver (P<0.05). HFD worsened olanzapine-induced weight gain and lipid metabolic disorders, possibly through ER stress-POMC and ER stress-NLRP3 signaling. ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.

Disentangling Dual Threats: Premature Coronary Artery Disease and Early-Onset Type 2 Diabetes Mellitus in South Asians.

South Asian individuals (SAs) face heightened risks of premature coronary artery disease (CAD) and early-onset type 2 diabetes mellitus (T2DM), with grave health, societal, and economic implications due to the region's dense population. Both conditions, influenced by cardiometabolic risk factors such as insulin resistance, hypertension, and central adiposity, manifest earlier and with unique thresholds in SAs. Epidemiological, demographic, nutritional, environmental, sociocultural, and economic transitions in SA have exacerbated the twin epidemic. The coupling of premature CAD and T2DM arises from increased obesity due to limited adipose storage, early-life undernutrition, distinct fat thresholds, reduced muscle mass, and a predisposition for hepatic fat accumulation from certain dietary choices cumulatively precipitating a decline in insulin sensitivity. As T2DM ensues, the β-cell adaptive responses are suboptimal, precipitating a transition from compensatory hyperinsulinemia to β-cell decompensation, underscoring a reduced functional β-cell reserve in SAs. This review delves into the interplay of these mechanisms and highlights a prediabetes endotype tied to elevated vascular risk. Deciphering these mechanistic interconnections promises to refine stratification paradigms, surpassing extant risk-prediction strategies.

(−)-Epigallocatechin-3-Gallate Reduces Perfluorodecanoic Acid-Exacerbated Adiposity and Hepatic Lipid Accumulation in High-Fat Diet-Fed Male C57BL/6J Mice

Perfluorodecanoic acid (PFDA), an enduring and harmful organic pollutant, is widely employed in diverse food-related sectors. Our previous studies have provided evidence that PFDA has the potential to facilitate obesity and hepatic fat accumulation induced by high-fat diet (HFD) intake. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, has been suggested to possess potential preventive effects against metabolic abnormalities and fatty liver. The purpose of this research was to investigate the effects of EGCG on PFDA-exacerbated adiposity and hepatic lipid accumulation in HFD-fed mice. The results showed that EGCG reduced body weight gain; tissue and organ weights; blood glucose, serum insulin, HOMA-IR, leptin, and lipid parameters; serum inflammatory cytokines (IL−1β, IL−18, IL−6, and TNF−α); and hepatic lipid accumulation in PFDA-exposed mice fed an HFD. Further work showed that EGCG improved liver function and glucose homeostasis in mice fed an HFD and co-exposed to PFDA. The elevated hepatic mRNA levels of SREBP-1 and associated lipogenic genes, NLRP3, and caspase−1 in PFDA-exposed mice fed an HFD were significantly decreased by EGCG. Our work provides evidence for the potential anti-obesity effect of EGCG on co-exposure to HFD and PFDA and may call for further research on the bioactivity of EGCG to attenuate the endocrine disruption effects of long-term exposure to pollutants.

A bioactive compound digested chia protein is capable of modulating NFκB mediated hepatic inflammation in mice fed a high-fat diet

The consumption of diets high in saturated fat can induce damages in liver morphology and function, which leads to increased inflammation, oxidative stress, and hepatic steatosis. Chia seed (Salvia hispanica L.) is rich in protein, which provides bioactive peptides with potential benefits, including antioxidant and anti-inflammatory functions. Then, this study aimed to analyze the effect of digested total protein (DTP) of chia on inflammation, oxidative stress, and morphological changes in liver of C57BL/6 mice fed a diet rich in saturated fat. Male C57BL/6 mice (n = 8/group), 8 weeks old, were fed standard diet (AIN), high-fat diet (HF), standard diet added digested protein (AIN + DTP) or high-fat diet added digested protein (HF + DTP) for 8 weeks. In animals fed a high-fat diet, chia DTP was able to reduce weight gain, food efficiency ratio and hepatosomatic index. In addition, it presented antioxidant capacity, which reduced catalase activity and lipid peroxidation. DTP was also able to reduce hepatic inflammation by reducing p65-NFκB expression and IL-1β expression and quantification. The APSPPVLGPP peptide present in chia DTP presented binding capacity with PPAR-α, which contributed to the reduction of hepatic fat accumulation evidenced by histological analysis. Thus, chia DTP improved hepatic inflammatory and histological parameters, being an effective food in reducing the liver damage caused by a high-fat diet.

The implication of neutrophil extracellular traps in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an expanding worldwide health concern, and the underlying mechanisms contributing to its progression still need further exploration. Neutrophil extracellular traps (NETs) are intricate formations comprised of nuclear constituents and diverse antimicrobial granules that are released into the extracellular milieu by activated neutrophils upon various triggers, which play a pivotal part in the onset and advancement of NAFLD. NETs actively participate in the genesis of NAFLD by fostering oxidative stress and inflammation, ultimately resulting in hepatic fat accumulation and the escalation of liver injury. Recent insights into the interaction with other hepatic immune populations and mediators, such as macrophages and T regulatory cells, have revealed several important mechanisms that can trigger further liver injury. In conclusion, the formation of NETs emerged as an important factor in the development of NAFLD, offering a promising target for innovative therapeutic approaches against this debilitating condition. This comprehensive review seeks to compile existing studies exploring the involvement of NETs in the genesis of NAFLD and their influence on the immune response throughout the progression of NAFLD.

Effects of diallyl disulfide administration on insulin resistance in high-fat diet-fed mice

ObjectivesDiallyl disulfide (DADS) is a natural organosulfur compound found in garlic and related plants with various pharmacologic effects. However, whether DADS improves obesity-induced insulin resistance (IR) and its underlying mechanisms remain unclear. The aim of this study was to investigate the effects of DADS on systemic IR in high-fat diet-induced obese mice. MethodsTo induce obesity, 8-wk-old male C57BL/6J mice were fed a high-fat diet (60% fat/kcal). The mice were assigned to three weight-matched groups: control (CON, n = 8), low-dose DADS (DADS-L, n = 8), and high-dose DADS (DADS-H, n = 9). The treated mice were orally administered DADS (25 or 100 mg/kg) 5 d/wk for 8 wk. At 15 wk of age, an intraperitoneal glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed. Twenty-four hours after the final administration of DADS, epididymal fat and the liver were sampled after a 5-h fast. ResultsDADS administration significantly attenuated body and fat weight gains during the experimental period. Additionally, systemic IR, as evaluated by ITT, was significantly improved by DADS administration in a dose-dependent manner. High-dose DADS administration significantly decreased liver triacylglycerol levels. Moreover, high-dose DADS administration decreased the c-Jun N-terminal kinase (JNK) phosphorylation and significantly increased heat shock protein 72 expression in the liver. ConclusionsThe results of this study suggested that DADS administration alleviated systemic IR in obese mice. This may be associated with decreased hepatic fat accumulation and a heat shock protein 72-mediated decrease in JNK activity in the liver.

Copine7 deficiency leads to hepatic fat accumulation via mitochondrial dysfunction

ObjectiveMitochondrial dysfunction affects hepatic lipid homeostasis and promotes ROS generation. Copine7 (CPNE7) belongs to the ubiquitous copine family of calcium-dependent phospholipid binding proteins. CPNE7 has a high calcium ion binding affinity and the capacity to scavenge reactive oxygen species (ROS). A recent study reported that abnormalities in fatty acid and lipid metabolism were linked to the gene variant of CPNE7. Therefore, the purpose of this study is to examine the role of Cpne7 in hepatic lipid metabolism based on mitochondrial function. MethodsLipid metabolism, mitochondrial function, and ROS production were investigated in high-fat diet (HFD)-fed Cpne7−/− mice and H2O2-damaged HepG2 hepatocytes following CPNE7 silencing or overexpression. ResultsCpne7 deficiency promoted severe hepatic steatosis in the HFD-induced NAFLD model. More importantly, mitochondrial dysfunction was observed along with an imbalance of mitochondrial dynamics in the livers of HFD-fed Cpne7−/−mice, resulting in high ROS levels. Similarly, CPNE7-silenced HepG2 hepatocytes showed high ROS levels, mitochondrial dysfunction, and increased lipid contents. On the contrary, CPNE7-overexpressed HepG2 cells showed low ROS levels, enhanced mitochondrial function and decreased lipid contents under H2O2-induced oxidative stress. ConclusionsIn the liver, Cpne7 deficiency causes excessive ROS formation and mitochondrial dysfunction, which aggravates lipid metabolism abnormalities. These findings provide evidence that Cpne7 deficiency contributes to the pathogenesis of NAFLD, suggesting Cpne7 as a novel therapeutic target for NAFLD.

Astaxanthin-enriched Oedocladium sp. improves liver health by enhancing fatty acid oxidation and suppressing inflammation in Trachinotus ovatus that was fed a high-fat diet

A high-fat diet can lead to fat deposition in the liver. Astaxanthin is reported to exert a hepatoprotective effect by affecting host fat metabolism. However, the molecular mechanism used by astaxanthin to regulate fat metabolism is still unclear. This study aimed to examine the function and molecular mechanism used by astaxanthin-enriched Oedocladium sp. in attenuating liver damage and fat deposition that was caused by a high-fat diet. The normal-fat diet (NF), high-fat diet (HF), and high-fat diet supplemented with Oedocladium sp. (HFO) were used to feed juvenile Trachinotus ovatus for 8 weeks. The findings of this study indicated that the HFO diet mitigated growth decline caused by the HF diet by improving digestibility and feed utilization. Meanwhile, the HFO diet reduced serum cholesterol and triglycerides as well as hepatic fat accumulation, alleviating inflammation, oxidative stress, and immunosuppression caused by an HF diet. Additionally, the HFO diet activated AMPK/ACC/CPT1 signal and suppressed the AMPK/SREBP1/FAS signal to promote the catabolism and transport of fat molecules and inhibit fat synthesis. This was regarded as an important regulatory mechanism that was used by Oedocladium sp. to alleviate the fat deposition induced by an HF diet. AMPK may be a key target for Oedocladium sp. to regulate fat metabolism. Therefore, Oedocladium sp., a promising source of astaxanthin, can be used in HF diets to enhance the health and productivity of farmed fish.

Green Pea (Pisum sativum L.) Hull Polyphenol Extract Alleviates NAFLD through VB6/TLR4/NF-κB and PPAR Pathways.

Green pea hull is a processing byproduct of green pea and rich in polyphenols. Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disease characterized by accumulation of lipids in the liver for which there are no effective treatment strategies. Here, a mouse model of NAFLD induced by a DSS+high-fat diet (HFD) was established to investigate the effect of green pea hull polyphenol extract (EGPH). The results show that EGPH relief of NAFLD was a combined effect, including reducing hepatic fat accumulation, improving antioxidant activity and blood lipid metabolism, and maintaining glucose homeostasis. Increased intestinal permeability aggravated NAFLD. Combined metabolomics and transcriptomic analysis showed that vitamin B6 is the key target substance for EGPH to alleviate NAFLD, and it may be the intestinal flora metabolite. After EGPH intervention, the level of vitamin B6 in mice was significantly increased, and more than 60% in the blood enters the liver, which activated or inhibited PPAR and TLR4/NF-κB signaling pathways to relieve NAFLD. Our research could be a win-win for expanding the use of green pea hull and the search for NAFLD prophylactic drugs.

Synergistic Effects of Chlorogenic Acid and Ganoderma Lucidum Polysaccharide on Hepatic Fat Accumulation

This study aimed to investigate the impact of different doses of chlorogenic acid and Ganoderma lucidum polysaccharide on lipid accumulation using an obese rat model. We utilized blood glucose assays, oil red O staining, and triglyceride content analysis to examine the effects of chlorogenic acid combined with G. lucidum polysaccharide on fat metabolism in rats. We found substantial potential in using chlorogenic acid combined with G. lucidum polysaccharide for weight control and metabolic regulation in obese rats. After a long-term dietary intervention, chlorogenic acid and G. lucidum polysaccharide markedly inhibited the expression of proteins related to fatty acid synthesis, including AMP-activated protein kinase, fatty acid synthase, and SREBP-1c, leading to reduced body weight and decreased hepatic fat deposition. Additionally, the combined treatment substantially affected enzymes and proteins involved in glucose metabolism, reducing glycogen synthase expression and indicating a potential mechanism for weight reduction through glycogen synthesis inhibition. Furthermore, elevated glucose kinase levels indicated that chlorogenic acid and G. lucidum polysaccharide may enhance hepatic glycogen degradation, thereby reducing hepatic fat accumulation. These findings reveal that chlorogenic acid combined with G. lucidum polysaccharide has a synergistic impact, providing a theoretical basis for their potential as a combined therapeutic approach for obesity.

Partial Replacement of Diet with Dehulled Adlay Ameliorates Hepatic Steatosis, Inflammation, Oxidative Stress, and Gut Dysbiosis in Rats with Nonalcoholic Fatty Liver Disease.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide, and the average age at NAFLD diagnosis has been decreasing. Although some components of adlay can ameliorate lipid metabolism, oxidative stress, inflammatory response, and gut microbiota, few studies have explored the effects of the dietary intake of intact dehulled adlay on liver diseases. Therefore, in this study, we investigated the effects of the dietary intake of dehulled adlay on NAFLD progression and explored the potential underlying mechanisms. Rats were randomized into a control group; a high-fat, high-sucrose diet (60% total energy derived from fat and 9.4% from sucrose)-induced NAFLD group (N); or a high-fat, high-sucrose diet with dehulled adlay group (received the same amounts of dietary fiber and total energy as did the N group). The experimental duration was 16 weeks. The diet containing dehulled adlay mitigated hepatic fat accumulation, proinflammatory cytokine levels, and oxidative stress by regulating the AMPK-Nrf2-NLRP3 inflammasome pathway and ferroptosis. Additionally, the dietary intake of dehulled adlay modulated the composition of the gut microbiota. In conclusion, a diet containing dehulled adlay may decelerate the progression of NAFLD by ameliorating hepatic steatosis, inflammation, oxidative stress, and gut dysbiosis.

Prebiotics and Probiotics: Therapeutic Tools for Nonalcoholic Fatty Liver Disease.

Alterations in the gut-liver axis and changes in the gut microbiome are among the risk factors for the pathogenesis of non-alcoholic fatty liver disease (NAFLD). These patients show increased bacterial overgrowth in the small intestine and impaired intestinal permeability. Therefore, therapeutic options such as probiotics or prebiotics have been investigated to modulate intestinal microbiota composition to improve NAFLD. Most in vivo and in vitro probiotic studies have focused on reducing hepatic fat accumulation. The beneficial effects of probiotics on NAFLD have been demonstrated in animal models, and the most widely used microorganisms are those of the Lactobacillus and Bifidobacterium genera. In animal models, probiotics help restore the intestinal microbiota and improve the integrity of the intestinal barrier. This narrative review summarizes published evidence and the likely benefits of probiotics and prebiotics as a therapeutic option for patients with NAFLD.

Long-term exposure to air pollution and prevalent nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a disease characterized by lipid accumulation within hepatocytes, ranging from simple steatosis to steatohepatitis, in the absence of secondary causes of hepatic fat accumulation. Although air pollution (AP) has been associated with several conditions related to NAFLD (e.g., metabolic syndrome, type 2 diabetes mellitus), few studies have explored an association between AP and NAFLD. The aim of the study was to investigate whether exposure to AP is associated with NAFLD prevalence. We used baseline cross-sectional data (2000-2003) of the Heinz-Nixdorf-Recall cohort study in Germany (baseline n = 4,814), a prospective population-based cohort study in the urbanized Ruhr Area. Mean annual exposure to size-fractioned particulate matter (PM10, PM2.5, PMcoarse, and PM2.5abs), nitrogen dioxide, and particle number was assessed using two different exposure models: a chemistry transport dispersion model, which captures urban background AP exposure on a 1 km2 grid at participant's residential addresses, and a land use regression model, which captures point-specific AP exposure at participant's residential addresses. NAFLD was assessed with the fatty liver index (n = 4,065), with NAFLD defined as fatty liver index ≥60. We estimated ORs of NAFLD per interquartile range of exposure using logistic regression, adjusted for socio-demographic and lifestyle variables. We observed a NAFLD prevalence of 31.7% (n = 1,288). All air pollutants were positively associated with NAFLD prevalence, with an OR per interquartile range for PM2.5 of 1.11 (95% confidence interval [CI] = 1.00, 1.24) using chemistry transport model, and 1.06 (95% CI = 0.94, 1.19) using the land use regression model, respectively. There was a positive association between long-term AP exposure and NAFLD.

Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism.

Nonalcoholic steatohepatitis (NASH) is a condition that progresses from nonalcoholic fatty liver disease (NAFLD) and is characterized by hepatic fat accumulation, inflammation, and fibrosis. It has the potential to develop into cirrhosis and liver cancer, and currently no effective pharmacological treatment is available. In this study, we investigate the therapeutic potential of targeting ceruloplasmin (Cp), a copper-containing protein predominantly secreted by hepatocytes, for treating NASH. Our result show that hepatic Cp is remarkedly upregulated in individuals with NASH and the mouse NASH model. Hepatocyte-specific Cp ablation effectively attenuates the onset of dietary-induced NASH by decreasing lipid accumulation, curbing inflammation, mitigating fibrosis, and ameliorating liver damage. By employing transcriptomics and metabolomics approaches, we have discovered that hepatic deletion of Cp brings about remarkable restoration of bile acid (BA) metabolism during NASH. Hepatic deletion of Cp effectively remodels BA metabolism by upregulating Cyp7a1 and Cyp8b1, which subsequently leads to enhanced BA synthesis and notable alterations in BA profiles. In conclusion, our studies elucidate the crucial involvement of Cp in NASH, highlighting its significance as a promising therapeutic target for the treatment of this disease.

Efficacy of SGLT2 Inhibitors Versus Pioglitazone in the Treatment of Non-alcoholic Fatty Liver Disease or Non-alcoholic Steatohepatitis: A Systematic Review.

Non-alcoholic fatty liver disease (NAFLD) is a complication related to obesity and metabolic syndrome. There are increased incidences of NAFLD/non-alcoholic steatohepatitis (NASH) due to rising obesity and type 2 diabetes mellitus (T2DM). This has resulted in significant morbidity and mortality. The two promising therapeutic agents for treating NAFLD/NASH are sodium-glucose cotransporter 2 (SGLT2) inhibitors and pioglitazone. The reason is their potential to target underlying pathophysiological mechanisms. SGLT2 inhibitors may help treat NAFLD/NASH by reducing insulin resistance and improving glucose control, thereby lowering hepatic fat accumulation and inflammation, although their exact mechanism in this context is still being studied. This systematic review aims to compare the efficacy of SGLT2 inhibitors and pioglitazone in treating NAFLD/NASH. Major research literature databases were searched, and appropriate keywords were used to find relevant articles published in the last three years. Eighteen studies were critically evaluated using standardized quality assessment tools. Among those, nine studies qualified as medium or high quality and were included in the review. Both SGLT2 inhibitors and pioglitazone showed promising results in improving NAFLD/NASH. The efficacy outcomes assessed liver fat content, liver enzyme levels, histological improvement, and metabolic parameters. The safety outcomes considered adverse events and cardiovascular events. The conducted review suggests that SGLT2 inhibitors and pioglitazone are potential treatment options for NAFLD/NASH. Having said that, individualized considerations are essential. It includes patient comorbidities, preferences, and overall safety profiles. Further research is needed to assess long-term effects and outcomes. It would provide more definitive evidence of these treatment options' comparative efficacy and safety for NAFLD/NASH.