Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with no approved drugs. High-protein dietary intervention is currently the most effective treatment. However, its underlying mechanism is unknown. Here, using Drosophila oenocytes, the specialized hepatocyte-like cells, we find that dietary essential amino acids ameliorate hepatic steatosis by inducing polyubiquitination of Plin2, a lipid droplet-stabilizing protein. Leucine and isoleucine, two branched-chain essential amino acids, strongly bind to and activate the E3 ubiquitin ligase Ubr1, targeting Plin2 for degradation. We further show that the amino acid-induced Ubr1 activity is necessary to prevent steatosis in mouse livers and cultured human hepatocytes, providing molecular insight into the anti-NAFLD effects of dietary protein/amino acids. Importantly, split-intein-mediated trans-splicing expression of constitutively active UBR2, an Ubr1 family member, significantly ameliorates obesity-induced and high fat diet-induced hepatic steatosis in mice. Together, our results highlight activation of Ubr1 family proteins as a promising strategy in NAFLD treatment.

Sugar-Sweetened Beverages and Adverse Human Health Outcomes: An Umbrella Review of Meta-Analyses of Observational Studies.

Our aim was to conduct an umbrella review of evidence from meta-analyses of observational studies investigating the link between sugar-sweetened beverage consumption and human health outcomes. Using predefined evidence classification criteria, we evaluated evidence from 47 meta-analyses encompassing 22,055,269 individuals. Overall, 79% of these analyses indicated direct associations between greater sugar-sweetened beverage consumption and higher risks of adverse health outcomes. Convincing evidence (class I) supported direct associations between sugar-sweetened beverage consumption and risks of depression, cardiovascular disease, nephrolithiasis, type 2 diabetes mellitus, and higher uric acid concentrations. Highly suggestive evidence (class II) supported associations with risks of nonalcoholic fatty liver disease and dental caries. Out of the remaining 40 meta-analyses, 29 were graded as suggestive or weak in the strength of evidence (classes III and IV), and 11 showed no evidence (class V). These findings inform and provide support for population-based and public health strategies aimed at reducing sugary drink consumption for improved health.

Adrenarche-accompanied rise of adrenal sex steroid precursors prevents NAFLD in Young Female rats by converting into active androgens and inactivating hepatic Srebf1 signaling.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease in children and adolescents, but its etiology remains largely unknown. Adrenarche is a critical phase for hormonal changes, and any disturbance during this period has been linked to metabolic disorders, including obesity and dyslipidemia. However, whether there is a causal linkage between adrenarche disturbance and the increasing prevalence of NAFLD in children remains unclear. RESULTS: Using the young female rat as a model, we found that the liver undergoes a transient slowdown period of growth along with the rise of adrenal-derived sex steroid precursors during adrenarche. Specifically blocking androgen actions across adrenarche phase using androgen receptor antagonist flutamide largely increased liver weight by 47.97% and caused marked fat deposition in liver, thus leading to severe NAFLD in young female rats. Conversely, further administrating nonaromatic dihydrotestosterone (DHT) into young female rats across adrenarche phase could effectively reduce liver fat deposition. But, administration of the aromatase inhibitor, formestane across adrenarche had minimal effects on hepatic de novo fatty acid synthesis and liver fat deposition, suggesting adrenal-derived sex steroid precursors exert their anti-NAFLD effects in young females by converting into active androgens rather than into active estrogens. Mechanistically, transcriptomic profiling and integrated data analysis revealed that active androgens converted from the adrenal sex steroid precursors prevent NAFLD in young females primarily by inactivating hepatic sterol regulatory element-binding transcription factor 1 (Srebf1) signaling. CONCLUSIONS: We firstly evidenced that adrenarche-accompanied rise of sex steroid precursors plays a predominant role in preventing the incidence of NAFLD in young females by converting into active androgens and inactivating hepatic Srebf1 signaling. Our novel finding provides new insights into the etiology of NAFLD and is crucial in developing effective prevention and management strategies for NAFLD in children.

Macrophage-derived Osteopontin (SPP1) Protects From Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether MF-derived OPN affects NASH progression is unknown. METHODS: We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose, and cholesterol diet mimicking the Western diet, to induce NASH. RESULTS: This study demonstrated that MFs with high expression of SPP1 are enriched in patients and mice with nonalcoholic fatty liver disease (NAFLD), and show metabolic but not pro-inflammatory properties. Conditional knockin of Spp1 in myeloid cells (Spp1KI Mye) or in hepatic macrophages (Spp1KI LvMF) conferred protection, whereas conditional knockout of Spp1 in myeloid cells (Spp1ΔMye) worsened NASH. The protective effect was mediated by induction of arginase-2 (ARG2), which enhanced fatty acid oxidation (FAO) in hepatocytes. Induction of ARG2 stemmed from enhanced production of oncostatin-M (OSM) in MFs from Spp1KI Mye mice. OSM activated STAT3 signaling, which upregulated ARG2. In addition to hepatic effects, Spp1KI Mye also protected through sex-specific extrahepatic mechanisms. CONCLUSION: MF-derived OPN protects from NASH, by upregulating OSM, which increases ARG2 through STAT3 signaling. Further, the ARG2-mediated increase in FAO reduces steatosis. Therefore, enhancing the OPN-OSM-ARG2 crosstalk between MFs and hepatocytes may be beneficial for patients with NASH.

BMAL1 deletion protects against obesity and non-alcoholic fatty liver disease induced by a high-fat diet.

OBJECTIVES: Obesity and non-alcoholic fatty liver disease (NAFLD) are major health concerns. The circadian rhythm is an autonomous and intrinsic timekeeping system closely associated with energy metabolism and obesity. Thus, this study explored the role of brain and muscle aryl hydrocarbon receptor nuclear translocator-like1 (BMAL1), a circadian clock regulator, in the development of obesity and NAFLD. METHODS: We generated BMAL1 knockout (BMAL1 KO) mice to imitate circadian rhythm disruption. The study comprised three groups from the same litter: BMAL1 KO mice fed a high-fat diet (to establish obesity and NAFLD phenotypes), wild-type mice fed normal chow, and wild-type mice fed a high-fat diet. The metabolic and NAFLD phenotypes were assessed via physiological measurements and histological examinations. Quantitative polymerase chain reaction and western blotting were used to identify and validate changes in the signaling pathways responsible for the altered NAFLD phenotypes in the wild-type and BMAL1 KO mice. RESULTS: BMAL1 depletion protected against obesity and metabolic disorders induced by a high-fat diet. BMAL1 depletion also prevented hepatic steatosis and inhibited cluster of differentiation 36 and peroxisome proliferator-activated receptor gamma (i.e., PPARγ) expression. CONCLUSIONS: BMAL1 plays an important role in the development of obesity and NAFLD and, thus, is a potential therapeutic target for these conditions.

Tripartite motif-containing protein 31 confers protection against nonalcoholic steatohepatitis by deactivating mitogen-activated protein kinase kinase kinase 7.

BACKGROUND AIMS: As a global health threat, NASH has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, mainly because its complicated pathological processes is underestimated. APPROACH RESULTS: We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of the E3 ubiquitin ligases family, as an efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48 linkage in hepatocytes. Hepatocyte-specific Trim31 deletion blocks hepatic metabolism homeostasis, concomitant with glucose metabolic syndrome, lipid accumulation, up-regulated inflammation, and dramatically facilitates NASH progression. Inversely, transgenic overexpression, lentivirus, or adeno-associated virus-mediated Trim31 gene therapy restrain NASH in three dietary mice models. Mechanistically, in response to metabolic insults, TRIM31 interacts with MAP3K7 and conjugates K48-linked ubiquitination chains to promote MAP3K7 degradation, thus blocking MAP3K7 abundance and its downstream signaling cascade activation in hepatocytes. CONCLUSIONS: TRIM31 may serve as a promising therapeutic target for NASH treatment and associated metabolic disorders.

Machine learning uncovers manganese as a key nutrient associated with reduced risk of steatotic liver disease.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 20%-30% of the general population and is linked to high-caloric western style diet. However, there are little data that specific nutrients might help to prevent steatosis. METHODS: We analysed the UK Biobank (ID 71300) 24 h-nutritional assessments and investigated the association between nutrient intake calculated from food questionnaires and hepatic steatosis indicated by imaging or ICD10-coding. The effect of manganese (Mn) on subgroups with risk single nucleotide polymorphism carriage as well as the effect on metabolomics was investigated. All analyses are corrected for age, sex, body mass index, Townsend index for socioeconomic status, kcal, alcohol, protein intake, fat intake, carbohydrate intake, energy from beverages, diabetes, physical activity and for multiple testing. RESULTS: We used a random forest classifier to analyse the feature importance of 63 nutrients and imaging-proven steatosis in a cohort of over 25 000 UK Biobank participants. Increased dietary Mn intake was associated with a lower likelihood of MRI-diagnosed steatosis. Subsequently, we conducted a cohort study in over 200 000 UK Biobank participants to explore the relationship between Mn intake and hepatic or cardiometabolic outcomes and found that higher Mn intake was associated with a lower risk of ICD-10 coded steatosis (OR = .889 [.838-.943], p < .001), independent of other potential confounders. CONCLUSION: Our study provides evidence that higher Mn intake may be associated with lower odds of steatosis in a large population-based sample. These findings underline the potential role of Mn in the prevention of steatosis, but further research is needed to confirm these findings and to elucidate the underlying mechanisms.

Preventive effects of caffeine on nicotine plus high-fat diet-induced hepatic steatosis and gain weight: a possible explanation for why obese smokers with high coffee consumption tend to be leaner.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder, affecting approximately 25 % of the population. Coffee-drinking obese smokers exhibit lower body weights and decreased NAFLD rates, but the reasons behind this remain unclear. Additionally, the effect of nicotine, the main component of tobacco, on the development of NAFLD is still controversial. Our study aimed to explore the possible reasons that drinking coffee could alleviate NAFLD and gain weight and identify the real role of nicotine in NAFLD of obese smokers. A NAFLD model in mice was induced by administering nicotine and a high-fat diet (HFD). We recorded changes in body weight and daily food intake, measured the weights of the liver and visceral fat, and observed liver and adipose tissue histopathology. Lipid levels, liver function, liver malondialdehyde (MDA), superoxide dismutase (SOD), serum inflammatory cytokine levels and the expression of hepatic genes involved in lipid metabolism were determined. Our results demonstrated that nicotine exacerbated the development of NAFLD and caffeine had a hepatoprotective effect on NAFLD. The administration of caffeine could ameliorate nicotine-plus-HFD-induced NAFLD by reducing lipid accumulation, regulating hepatic lipid metabolism, alleviating oxidative stress, attenuating inflammatory response and restoring hepatic functions. These results might explain why obese smokers with high coffee consumption exhibit the lower incidence rate of NAFLD and tend to be leaner. It is essential to emphasise that the detrimental impact of smoking on health is multifaceted. Smoking cessation remains the sole practical and effective strategy for averting the tobacco-related complications and reducing the risk of mortality.

Delivery of a telehealth supported home exercise program with dietary advice to increase plant-based protein intake in people with non-alcoholic fatty liver disease: a 12-week randomised controlled feasibility trial.

This study evaluated the feasibility and safety of a telehealth delivered exercise plus plant-based protein diet in adults with non-alcoholic fatty liver disease (NAFLD). This was a 12-week, randomised controlled feasibility trial including twenty-eight adults aged > 45 years with NAFLD randomised to a home muscle strengthening program (3 d/week) with increased protein intake (target ∼1·2-1·5 g/kg/d) from predominately plant-based sources and behavioural change support (3-4 text messages/week) (Pro-Ex n 14) or usual care (UC, n 14). Feasibility was assessed via retention (≤ 10 % attrition), adherence (exercise ≥ 66 %; recommended daily protein serves ≥ 80 %) and safety (adverse events). Secondary outcomes included macronutrient intake (3 × 24-h records), weight, moderate-to-vigorous physical activity (MVPA) and 30 s sit-to-stand (STS) performance. Study retention was 89 %. Mean exercise adherence (Pro-Ex) was 52 % with one adverse event from 241 sessions. In Pro-Ex, mean daily plant protein serves increased (0·9 to 1·4/d) and animal protein decreased (1·5 to 1·2/d) after 12-weeks, but overall adherence (serves/day) was 32[RD1] % (plant) and 42 % (animal). Relative to UC, Pro-Ex experienced a mean 2·7 (95 % CI: 0·9, 4·4) increase in 30 s STS number, 46-minute (95 % CI: -153, 245) increase in MVPA, 1·7 kg (95 % CI: -3·5, 0·2) decrease in weight, 35·2 g (95 % CI: 11·0, 59·3) increase in protein. In adults with NAFLD a telehealth home exercise and dietary intervention was safe and improved habitual plant and animal protein intake, but overall adherence was modest suggesting more intensive healthcare support may be required.

Anti-inflammatory diet reduces risk of metabolic dysfunction-associated fatty liver disease among US adults: a nationwide survey.

BACKGROUND: While dietary intervention was an important public health strategy for the prevention and intervention of metabolic dysfunction-associated fatty liver disease (MAFLD), the effect of diet-induced inflammation on MAFLD has not been studied in detail. Therefore, we aimed to analyze the relationship between dietary inflammatory index (DII) and MAFLD. METHODS: This study included data from the National Health and Nutrition Examination Survey 2017-2018. MAFLD was diagnosed based on the presence of hepatic steatosis, as determined by transient elastography, along with evidence of either overweight/obesity, type 2 diabetes mellitus, or metabolic dysfunction. DII was calculated using 27 dietary components collected through 24-hour dietary recall questionnaire. Weighted logistic regression was used to analyze the relationship between DII and MAFLD and its main components in three different models. Subgroup analyses were performed by age, sex, and alcohol use. RESULTS: A total of 1991 participants were included, and the MAFLD group had higher DII scores. After adjusting for age, sex, race, physical activity, smoking status, and alcohol use, the highest quartile of DII was associated with increased risk of MAFLD (OR:2.90, 95% CIs: 1.46, 5.75). Overweight/obesity, central obesity, low high density lipoprotein cholesterol (HDL-C) and high C-reactive protein (CRP) also shared the same characteristics in the main components of MAFLD. Results were consistent across subgroups (age, sex, and alcohol use). CONCLUSIONS: A higher DII diet was positively associated with the risk of MAFLD in American adults, particularly as related to overweight/obesity, central obesity, high CRP level, and low HDL-C level.

Protective effects of syringic acid in nonalcoholic fatty liver in rats through regulation of Nrf2/HO-1 signaling pathway.

Nonalcoholic fatty liver disease (NAFLD) is an alarming ailment that leads to severe liver damage and increases the risk of serious health conditions. The prevalence of NAFLD due to oxidative stress could be mitigated by plant-derived antioxidants. This study aims to investigate the effects of syringic acid (SA) on NAFLD in a high-fat diet (HFD) rat model. Twenty-four rats were randomly divided into four groups (n = 6): normal control, HFD, SA-administered HFD, and positive control SA on a normal diet. Rats in the normal control and positive control groups received a normal diet, and the remaining groups received an HFD for 8 weeks. SA (20 mg/kg b.w.) was orally (gavage) administered for 8 weeks. Lipid profiles were controlled by SA against HFD-fed rats (p < 0.05). SA reduced the serum aspartate aminotransferase and alanine aminotransferase levels by 70%-190%. SA also suppressed pro-inflammatory cytokines and attenuated histopathological and immunohistochemical changes against HFD-fed rats. SA reversed oxidative stress by suppressing the malondialdehyde formation by 82% and replenished the nonenzymatic and enzymatic antioxidant activities (p < 0.05). Gene expressions of nuclear factor-erythroid 2-related factor/heme oxygenase 1 (Nrf2/HO-1) were elevated in SA-treated rats. Ameliorative effects of SA on NAFLD induced by an HFD in rats were prominent through the reversal of oxidative stress and inflammation, regulated by an intrinsic mechanism of defense against oxidative stress, the Nrf2/HO-1 pathway.

Coprococcus protects against high-fat diet-induced nonalcoholic fatty liver disease in mice.

AIMS: The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing annually, leading to substantial medical and health burdens. Numerous studies have demonstrated the potential effectiveness of intestinal probiotics as a treatment strategy for NAFLD. Therefore, the objective of this study is to identify a probiotic for the treatment of NAFLD. METHODS AND RESULTS: In this study, blood and fecal samples were collected from 41 healthy volunteers and 44 patients diagnosed with NAFLD. Analysis of the 16S rDNA sequencing data and quantitative real-time PCR (RT-qPCR) revealed a significant reduction in the abundance of Coprococcus in NAFLD patients. Subsequent animal experiments demonstrated that Coprococcus was able to effectively reverse liver lipid accumulation, inflammation, and fibrosis induced by a high-fat diet (HFD) in mice. CONCLUSIONS: This study provides the first in vivo evidence that Coprococcus is a beneficial bacterium capable of preventing NAFLD and has the same probiotic effect in mice as Lactobacillus GG (LGG), a positive control. Therefore, Coprococcus has the potential to serve as a probiotic for the prevention and treatment of NAFLD in humans.

De novo NAD+ synthesis enhances mitochondrial function and improves health.

Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here we show that α-amino-ß-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-ß-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. We also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, we identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.

Olive Oil's Attenuating Effects on Lipotoxicity.

Dietary fatty acids play a role in the pathogenesis of obesity-associated nonalcoholic fatty liver disease. Lipotoxicity in obesity mediates insulin resistance, endothelial dysfunction, atherosclerosis, and gut microbiota dysbiosis. Cardiovascular complications are the main cause of morbidity and mortality in obese, insulin-resistant, and type 2 diabetes mellitus patients.Interventions targeting lipotoxicity are the main issue in preventing its multiple insults. Lifestyle modifications including healthy eating and regular exercise are the primary recommendations. Treatments also include drugs targeting energy intake, energy disposal, lipotoxic liver injury, and the resulting inflammation, fibrogenesis, and cirrhosis.Diet and nutrition have been linked to insulin resistance, an increased risk of developing type 2 diabetes, and impaired postprandial lipid metabolism. Low-fat diets are associated with higher survival. The Mediterranean diet includes an abundance of olive oil. Extra-virgin olive oil is the main source of monounsaturated fatty acids in Mediterranean diets. An olive oil-rich diet decreases triglyceride accumulation in the liver, improves postprandial triglyceride levels, improves glucose and insulin secretions, and upregulates GLUT-2 expression in the liver. The exact molecular mechanisms of olive oil's effects are unknown, but decreasing NF-kB activation, decreasing LDL oxidation, and improving insulin resistance by reducing the production of inflammatory cytokines (TNF-α and IL-6) and upregulating kinases and JNK-mediated phosphorylation of IRS-1 are possible principal mechanisms. Olive oil phenolic compounds also modulate gut microbiota diversity, which also affects lipotoxicity.In this review, we document lipotoxicity in obesity manifestations and the beneficial health effects of the Mediterranean diet derived from monounsaturated fatty acids, mainly from olive oil.

Flavonoids and Their Role in Preventing the Development and Progression of MAFLD by Modifying the Microbiota.

With the increasing prevalence and serious health consequences of metabolic-associated fatty liver disease (MAFLD), early diagnosis and intervention are key to effective treatment. Recent studies highlight the important role of dietary factors, including the use of flavonoids, in improving liver health. These compounds possess anti-inflammatory, antioxidant, and liver-protective properties. Flavonoids have been shown to affect the gut microbiota, which plays a key role in liver function and disease progression. Therefore, their role in preventing the development and progression of MAFLD through modulation of the microbiome seems to be of interest. This narrative review aims to consolidate the current evidence on the effects of selected flavonoids on MAFLD progression, their potential mechanisms of action, and the implications for the development of personalized dietary interventions for the management of liver disease.

Effects of Interventions for Improving Awareness and Knowledge of Nonalcoholic Fatty Liver Disease Among Chinese Young Adults for Prevention of Liver Cancer-A Randomized Controlled Trial.

Chinese young adults (CYA), who are at an increasing risk of developing nonalcoholic fatty liver disease (NAFLD), which in turn increases the risk of liver cancer, are an ideal target population to deliver educational interventions to improve their awareness and knowledge of NAFLD and consequently reduce their risk of developing NAFLD. The purpose of this study was to determine the efficacy of two interventions to improve awareness and knowledge of NAFLD among CYA for the prevention of liver cancer. Between May and July 2021, 1373 undergraduate students aged 18 to 25 years in one university in China completed a web-based, self-administered survey distributed through WeChat app. One week after completion of the baseline survey, all eligible participants were randomly assigned to a pamphlet, a video intervention, or no intervention (control group), with follow-up assessments immediately and 1-month post-intervention. The 7-page pamphlet or 6.5-min video had information on NAFLD. Self-assessments included NAFLD awareness, lean NAFLD awareness, and knowledge scores of NAFLD. About 26% of participants had NAFLD awareness at baseline. Compared with controls, participants in both interventions showed significant improvement of awareness of NAFLD (pamphlet, + 46.0%; video, + 44.3%; control, + 18.7%; OR [95% CI], 3.13 [2.19-4.47] and 2.84 [1.98-4.08]), awareness of lean NAFLD (pamphlet, + 41.2%; video, + 43.0%; control, + 14.5%; OR [95% CI], 2.84 [1.62-4.99] and 2.61 [1.50-4.54]), and knowledge score of NAFLD (pamphlet, + 64.2%; video, + 68.9%; control, - 1.0%; OR [95% CI], 1.62 [1.47-1.80] and 1.67 [1.50-1.86]) at immediately post-intervention. Delivering NAFLD education through a pamphlet or video intervention was effective in improving the awareness and knowledge of NAFLD among CYA.

Proanthocyanidins-Based Synbiotics as a Novel Strategy for Nonalcoholic Fatty Liver Disease (NAFLD) Risk Reduction.

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, is a spectrum of liver abnormalities ranging from steatosis to nonalcoholic steatohepatitis (NASH) characterized by excessive lipid accumulation. The prevalence of NAFLD is predicted to increase rapidly, demanding novel approaches to reduce the global NAFLD burden. Flavonoids, the most abundant dietary polyphenols, can reduce the risk of NAFLD. The majority of dietary flavonoids are proanthocyanidins (PACs), which are oligomers and polymers of the flavonoid sub-group flavan-3-ols. The efficacy of PAC in reducing the NAFLD risk can be significantly hindered by low bioavailability. The development of synbiotics by combining PAC with probiotics may increase effectiveness against NAFLD by biotransforming PAC into bioavailable metabolites. PAC and probiotic bacteria are capable of mitigating steatosis primarily through suppressing de novo lipogenesis and promoting fatty acid ß-oxidation. PAC and probiotic bacteria can reduce the progression of steatosis to NASH mainly through ameliorating hepatic damage and inflammation induced by hepatic oxidative stress, endoplasmic reticulum stress, and gut microbiota dysbiosis. Synbiotics of PAC are superior in reducing the risk of NAFLD compared to independent administration of PAC and probiotics. The development of PAC-based synbiotics can be a novel strategy to mitigate the increasing incidence of NAFLD.

Oleuropein mitigates non-alcoholic fatty liver disease (NAFLD) and modulates liver metabolites in high-fat diet-induced obese mice via activating PPARα.

BACKGROUND: This study aimed to elucidate the mechanism of oleuropein (OLE) ameliorates non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms. RESULTS: Male C57BL/6J mice were fed either a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.03% (w/w) OLE for 16 weeks. OLE supplementation decreased body weight and liver weight, improved serum lipid profiles, and ameliorated HFD-induced hepatic dysfunction. Liver metabolomics analysis revealed that OLE increased the levels of nicotinamide, tauroursodeoxycholic acid, taurine, and docosahexaenoic acid, which were beneficial for lipid homeostasis and inflammation regulation. OLE exerted its protective effects by activating peroxisome proliferator-activated receptor alpha (PPARα), a key transcription factor that regulates fibroblast growth factor 21 (FGF21) expression and modulates lipid oxidation, lipogenesis and inflammation pathways. Importantly, OLE supplementation did not significantly affect body weight or liver weight in PPARα knockout (PPARα KO) mice, indicating that PPARα is essential for OLE-mediated NAFLD prevention. CONCLUSION: Our results suggest that OLE alleviates NAFLD in mice by activating PPARα and modulating liver metabolites. © 2024 Society of Chemical Industry.

Lauric acid attenuates hepato-metabolic complications and molecular alterations in high-fat diet-induced nonalcoholic fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver illness characterized by increase of lipid content in the liver. This study investigated the role of lauric acid to treat NAFLD in male adult Sprague Dawley rats. In this study, to induce NAFLD in the rats, a high-fat diet (HFD) was administered for eight consecutive weeks. Lauric acid groups received lauric acid (250 and 500 mg/kg; orally), concurrently with HFD for eight consecutive weeks. Lauric acid could ameliorate the serum levels of TG, TC, ALT, AST, blood glucose, and insulin. Moreover, lauric acid significantly elevated the levels of SOD, GSH, catalase, and IL-10. Additionally, it lowered the hepatic levels of MDA, ROS, MPO, 4-HNE, interleukin (IL)-1ß, and tumor necrosis factor (TNF-α). Furthermore, lauric acid significantly up-regulated the hepatic expression of IRS1, AMPK, PI3K, and SIRT1 genes. In parallel, lauric acid could improve the histopathological picture of the liver and reduce the liver apoptosis via decreasing the expression of annexin V (Anx V). Finally, our data proposed that lauric acid could be an effective candidate for the NAFLD treatment.

[Guidelines for the prevention and treatment of metabolic dysfunction-associated (non-alcoholic) fatty liver disease (Version 2024)].

The Chinese Society of Hepatology of the Chinese Medical Association invited relevant experts to revise and update the Guideline of Prevention and Treatment of Nonalcoholic Fatty Liver Disease (2018Version) and renamed it as (Version 2024) Guideline for the Prevention and Treatment of Metabolic Dysfunction-associated (non-alcoholic) Fatty Liver Disease. Herein, the guiding recommendations on clinical issues such as screening and monitoring, diagnosis and evaluation, treatment and follow-up of metabolic dysfunction-associated fatty liver disease are put forward.