High-fat diet, gut dysbiosis, and oxidative stress: A synergistic triangle in metabolic dysfunction-associated steatotic liver disease pathogenesis

Expanding the liver exposome: Should hepatologists care about air pollution?

Changing Nomenclature from Nonalcoholic Fatty Liver Disease to Metabolic Dysfunction-Associated Fatty Liver Disease – Not Only Premature But Also Confusing

Adipocyte death has been reported in both obese humans and rodents. However, its role in metabolic disorders, including insulin resistance, hepatic steatosis, and inflammation associated with obesity has not been studied. We now show using real-time reverse transcription-PCR arrays that adipose tissue of obese mice display a pro-apoptotic phenotype. Moreover, caspase activation and adipocyte apoptosis were markedly increased in adipose tissue from both mice with diet-induced obesity and obese humans. These changes were associated with activation of both the extrinsic, death receptor-mediated, and intrinsic, mitochondrial-mediated pathways of apoptosis. Genetic inactivation of Bid, a key pro-apoptotic molecule that serves as a link between these two cell death pathways, significantly reduced caspase activation, adipocyte apoptosis, prevented adipose tissue macrophage infiltration, and protected against the development of systemic insulin resistance and hepatic steatosis independent of body weight. These data strongly suggest that adipocyte apoptosis is a key initial event that contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis associated with obesity in both mice and humans. Inhibition of adipocyte apoptosis may be a new therapeutic strategy for the treatment of obesity-associated metabolic complications.

Empagliflozin (EMPA)-a sodium-glucose cotransporter type 2 inhibitor-reduces endoplasmic reticulum (ER) stress, oxidative stress, and inflammation during metabolic dysfunction-associated steatotic liver disease (MASLD) progression. However, the direct effects of EMPA on hepatic lipid metabolism and oxidative stress are unclear. Through the current study, we seek to explore the effects of EMPA on oxidative stress and related mechanisms in MASLD. To this end, MASLD was induced in C57BL/6J mice using a high-fat diet (HFD); nuclear respiratory factor 1 (NRF1) was downregulated via viral transduction (AAV8-shNrf1). Glucose homeostasis and liver histology were assessed, and oxidative stress and inflammation were measured. HFD-fed mice-derived liver tissue samples exhibited more lipid droplets, higher triglyceride levels, and elevated oxidative and ER stress than chow diet (CD)-fed mice. EMPA attenuated HFD-induced liver oxidative and ER stress. Additionally, the HFD significantly decreased NRF1 and Sirtuin (SIRT)7 expression compared with CD, which was rescued by EMPA treatment. However, these results did not affect insulin resistance or lipid synthesis-related changes upon EMPA treatment in the Nrf1-knockdown mice. Furthermore, EMPA alleviated HFD-induced hepatic steatosis and oxidative stress; however, these effects were lost in Nrf1-knockdown mice. Collectively, the results of this study suggest that EMPA ameliorates MASLD by reducing steatosis and attenuating oxidative stress via NRF1.

Yet more evidence that MAFLD is more than a name change

Gut dysbiosis develops before metabolic disturbance and cognitive decline in high-fat diet-induced obese condition.

Non-alcoholic fatty liver disease: Not time for an obituary just yet!

Targeting DUSP7 signaling alleviates hepatic steatosis, inflammation and oxidative stress in high fat diet (HFD)-fed mice via suppression of TAK1

Gut dysbiosis, resulting from an imbalance in the gut microbiome, can induce excessive production of reactive oxygen species (ROS), leading to inflammation, DNA damage, activation of the immune system, and epigenetic alterations of critical genes involved in the metabolic pathways. Gut dysbiosis-induced inflammation can also disrupt the gut barrier integrity and increase intestinal permeability, which allows gut-derived toxic products to enter the liver and systemic circulation, further triggering oxidative stress, inflammation, and epigenetic alterations associated with metabolic diseases. However, specific gut-derived metabolites, such as short-chain fatty acids (SCFAs), lactate, and vitamins, can modulate oxidative stress and the immune system through epigenetic mechanisms, thereby improving metabolic function. Gut microbiota and diet-induced metabolic diseases, such as obesity, insulin resistance, dyslipidemia, and hypertension, can transfer to the next generation, involving epigenetic mechanisms. In this review, we will introduce the key epigenetic alterations that, along with gut dysbiosis and ROS, are engaged in developing metabolic diseases. Finally, we will discuss potential therapeutic interventions such as dietary modifications, prebiotics, probiotics, postbiotics, and fecal microbiota transplantation, which may reduce oxidative stress and inflammation associated with metabolic syndrome by altering gut microbiota and epigenetic alterations. In summary, this review highlights the crucial role of gut microbiota dysbiosis, oxidative stress, and inflammation in the pathogenesis of metabolic diseases, with a particular focus on epigenetic alterations (including histone modifications, DNA methylomics, and RNA interference) and potential interventions that may prevent or improve metabolic diseases.

BackgroundConsuming prebiotics demonstrated therapeutic potential against obesity, as illustrated by our previous study on xylooligosaccharide (XOS), revealing that XOS reduced adiposity, diminished systemic inflammation, and restored cognitive function in obese insulin‐resistant rats through the gut‐brain axis. Fresh bananas at various ripening stages are being transformed into snacks, indicating potential as prebiotic‐based treats enriched with fructooligosaccharide and inulin. Despite those findings, there remains a notable gap in the literature concerning the impact of these prebiotic‐based snacks on brain inflammation, reactive oxygen species (ROS) production, and cognitive function in high‐fat diet (HFD)‐induced obese rats.MethodSeventy‐two male rats were divided into two groups, receiving either a normal diet (ND) or an HFD for total 16 weeks. At 13th week, ND‐fed rats were randomly assigned to 6 subgroups (n = 6/group) to receive either vehicle (NDV, 21 ml/kg/day), prebiotic‐based snacks prepared from bananas at ripening stages 2‐5 (NDS2‐5) (7.47 g dissolved in reversed osmosis water, 21 ml/kg/day in each subgroup), and inulin (NDI, 2 g/kg/day). Similarly, HFD‐fed rats were divided into 6 subgroups (n = 6/group): HFD‐fed rats receiving vehicle (HFV), prebiotic‐based snacks prepared from bananas at ripening stages 2‐5 (HFS2‐5) and inulin, with the same dose as ND‐fed rats, for 4 weeks. Cognitive function was assessed by novel object recognition (NOR). Serum malondialdehyde (MDA) levels, gut microbiota, brain inflammation, and brain ROS production were determined at the end of treatment.ResultThe HFV group exhibited elevated serum MDA levels, increased brain mitochondrial ROS production, heightened TNF‐α levels, indicating brain inflammation, and an augmented Firmicutes to Bacteroidetes (F/B) ratio, indicating gut dysbiosis, when compared to the NDV group (p<0.05, Figure 1). Additionally, the HFV group showed cognitive decline, evidenced by a reduced percentage preference index in the NOR test (p<0.05, Figure 1). Remarkably, HFV rats receiving a prebiotic‐based snack showed reduced serum MDA levels, brain mitochondrial ROS production, brain inflammation, and improved gut dysbiosis, resulting in enhanced cognitive function. (p<0.05, Figure 1).ConclusionA prebiotic‐based snack at all ripening stages holds promise as a neuroprotection against HFD‐induced obesity, offering multifaceted benefits by mitigating oxidative stress, gut dysbiosis, brain inflammation, and attenuated cognitive dysfunction in HFD‐fed rats.

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and fish oil are considered to be a part of healthy diets. However, their differential effects on gut microbiome perturbations in mice fed high concentrations of these fats, in the absence of sucrose, remains to be elucidated. The aim of the study was to test whether the sucrose-free cocoa butter-based high-fat diet (C-HFD) feeding in mice leads to gut dysbiosis that associates with a pathologic phenotype marked by hepatic steatosis, low-grade inflammation, perturbed glucose homeostasis, and insulin resistance, compared with control mice fed the fish oil based high-fat diet (F-HFD). C57BL/6 mice (5-6 mice/group) were fed two types of high fat diets (C-HFD and F-HFD) for 24 weeks. No significant difference was found in the liver weight or total body weight between the two groups. The 16S rRNA sequencing of gut bacterial samples displayed gut dysbiosis in C-HFD group, with differentially-altered microbial diversity or relative abundances. Bacteroidetes, Firmicutes, and Proteobacteria were highly abundant in C-HFD group, while the Verrucomicrobia, Saccharibacteria (TM7), Actinobacteria, and Tenericutes were more abundant in F-HFD group. Other taxa in C-HFD group included the Bacteroides, Odoribacter, Sutterella, Firmicutes bacterium (AF12), Anaeroplasma, Roseburia, and Parabacteroides distasonis. An increased Firmicutes/Bacteroidetes (F/B) ratio in C-HFD group, compared with F-HFD group, indicated the gut dysbiosis. These gut bacterial changes in C-HFD group had predicted associations with fatty liver disease and with lipogenic, inflammatory, glucose metabolic, and insulin signaling pathways. Consistent with its microbiome shift, the C-HFD group showed hepatic inflammation and steatosis, high fasting blood glucose, insulin resistance, increased hepatic de novo lipogenesis (Acetyl CoA carboxylases 1 (Acaca), Fatty acid synthase (Fasn), Stearoyl-CoA desaturase-1 (Scd1), Elongation of long-chain fatty acids family member 6 (Elovl6), Peroxisome proliferator-activated receptor-gamma (Pparg) and cholesterol synthesis (β-(hydroxy β-methylglutaryl-CoA reductase (Hmgcr). Non-significant differences were observed regarding fatty acid uptake (Cluster of differentiation 36 (CD36), Fatty acid binding protein-1 (Fabp1) and efflux (ATP-binding cassette G1 (Abcg1), Microsomal TG transfer protein (Mttp) in C-HFD group, compared with F-HFD group. The C-HFD group also displayed increased gene expression of inflammatory markers including Tumor necrosis factor alpha (Tnfa), C-C motif chemokine ligand 2 (Ccl2), and Interleukin-12 (Il12), as well as a tendency for liver fibrosis. These findings suggest that the sucrose-free C-HFD feeding in mice induces gut dysbiosis which associates with liver inflammation, steatosis, glucose intolerance and insulin resistance.

Geniposidic acid alleviated metabolic dysfunction-associated steatotic liver disease by exciting SIRT6 signaling.

Chitosan and chito-oligosaccharides as multifunctional therapeutics for metabolic dysfunction-associated steatotic liver disease (MASLD).

Biosynthesis of hepatic choline via phosphatidylethanolamine N-methyltransferase (PEMT) plays an important role in the development of type 2 diabetes and obesity. We investigated the mechanism(s) by which choline modulates insulin sensitivity. PEMT wild-type (Pemt(+/+)) and knock-out (Pemt(-/-)) mice received either a high fat diet (HF; 60% kcal of fat) or a high fat, high choline diet (HFHC; 4 g of choline/kg of HF diet) for 1 week. Hepatic insulin signaling and glucose and lipid homeostasis were investigated. Glucose and insulin intolerance occurred in Pemt(-/-) mice fed the HFHC diet, but not in their Pemt(-/-) littermates fed the HF diet. Plasma glucagon was elevated in Pemt(-/-) mice fed the HFHC diet compared with Pemt(-/-) mice fed the HF diet, concomitant with increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and phosphorylated insulin receptor substrate 1 at serine 307 (IRS1-s307). Gluconeogenesis and mitochondrial oxidative stress were markedly enhanced, whereas glucose oxidation and triacylglycerol biosynthesis were diminished in Pemt(-/-) mice fed the HFHC diet. A glucagon receptor antagonist (2-aminobenzimidazole) attenuated choline-induced hyperglycemia and insulin intolerance and blunted up-regulation of phosphorylated AMPK and IRS1-s307. Choline induces glucose and insulin intolerance in Pemt(-/-) mice through modulating plasma glucagon and its action in liver.