Metabolic syndrome (MetS) is a disease with complex and diverse etiologies. Extrinsic factors such as diet and lifestyle can induce dysbiosis of gut microbes, compromising intestinal barrier integrity and leading to inflammation and insulin resistance, thereby advancing MetS. Probiotic interventions have shown potential in ameliorating gut microbiota dysbiosis and regulating host metabolism by assimilating lipids, metabolizing carbohydrates, and producing short-chain fatty acids (SCFA), indole compounds, secondary bile acids, conjugated linoleic acid (CLA), and other active ingredients. An increasing number of new strains are being isolated and validated for their effective roles intervening on MetS in animal and population studies. This review aims to provide updated insights into the pathogenic mechanisms of MetS, highlight the newly identified probiotic strains that have demonstrated improvements in MetS, and elucidate their mechanisms of action, with the aim of offering contemporary perspectives for the future use of probiotics in mitigating MetS.

Hepatocellular carcinoma (HCC) is among the most aggressive malignancies, marked by high recurrence rates and limited treatment efficacy, especially in HBV-associated HCC (HBV-HCC). This subtype exhibits pronounced metabolic reprogramming, with lipid synthesis playing a pivotal role in driving tumor aggressiveness and therapeutic resistance. However, the molecular mechanisms underlying this metabolic shift remain unclear. In our study, analysis of the LIHC-TCGA database and comparisons between HCC tissues and adjacent peri-tumoral tissues revealed that 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is significantly upregulated in HBV-HCC. Moreover, elevated PFKFB4 expression correlates with poorer prognosis and unfavorable overall survival among HBV-HCC patients. Functional assays demonstrated that PFKFB4 promotes HCC proliferation by enhancing glycolysis and de novo lipid synthesis. Notably, PFKFB4 not only increases glycolytic flux but also upregulates sterol regulatory element-binding protein 1 (SREBP1) expression via its enzymatic activity. Mechanistically, PFKFB4 suppresses phosphorylated AMP-activated protein kinase (p-AMPK) through enhanced aerobic glycolysis, which in turn stimulates the level of SREBP1. Collectively, these findings position PFKFB4 as a critical mediator of metabolic reprogramming in HBV-HCC and a promising therapeutic target.

Non-energetic roles for glucose are largely unclear, as is the interplay between transcription factors (TFs) and ubiquitous biomolecules. Metabolomic analyses uncovered elevation of intracellular glucose during differentiation of diverse cell types. Human and mouse tissue engineered with glucose sensors detected a glucose gradient that peaked in the outermost differentiated layers of the epidermis. Free glucose accumulation was essential for epidermal differentiation and required the SGLT1 glucose transporter. Glucose affinity chromatography uncovered glucose binding to diverse regulatory proteins, including the IRF6 TF. Direct glucose binding enabled IRF6 dimerization, DNA binding, genomic localization, and induction of IRF6 target genes, including essential pro-differentiation TFs GRHL1, GRHL3, HOPX, and PRDM1. These data identify a role for glucose as a gradient morphogen that modulates protein multimerization in cellular differentiation.

Fructose, a common sweetener in modern diets, has profound effects on both metabolism and brain function, primarily due to its distinct metabolic pathways. Unlike glucose, fructose bypasses critical regulatory steps in metabolism, particularly the phosphofructokinase-1 (PFK-1) feedback inhibition, leading to uncontrolled metabolism and increased fat storage. This review delves into the metabolic consequences of fructose consumption, including its limited role in directly stimulating insulin secretion, which affects satiety signaling and contributes to increased food intake. The small intestine initially helps metabolize ingested fructose, shielding the liver and brain from excessive exposure. However, when consumed in excess, particularly in diets high in processed foods, this protective mechanism becomes overwhelmed, contributing to metabolic disorders such as insulin resistance, obesity, and fatty liver disease. The review also explores fructose's impact on the brain, with a focus on the hippocampus, a key region for memory and learning. Chronic high fructose intake has been linked to mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and neuroinflammation, all of which contribute to cognitive decline and impairments in memory and learning. Additionally, fructose-induced alterations in insulin signaling in the brain are associated with increased risk for neurodegenerative diseases. These findings underscore the potential long-term neurological consequences of excessive fructose intake and highlight the need for further human studies to assess the full spectrum of its effects on brain health. Addressing the rising consumption of fructose, particularly in processed foods, is essential for developing targeted strategies to mitigate its adverse metabolic and cognitive outcomes.

Many traditional treatments include honey owing to its magnificent health beneficiary effects. Recent studies have demonstrated the potent anti-diabetic activity of honey. However, its actual mechanism of action remains elusive. Moreover, being rich in sugar (75%-80%), its role in maintaining glucose homeostasis remains questionable. Although the polyphenol content of honey aids its hypoglycaemic activity, the small quantity of bioactive compounds in honey (0.5%-1.0%) may not be solely responsible for this. In the current study, an attempt was made to understand the role of Indian lychee honey (LyH) in regulating blood glucose levels under diabetic conditions. This study investigated whether LyH, although rich in sugars, can be used as an alternative to regulate glucose and lipid homeostasis under insulin-resistant conditions by regulating the ChREBP/Glut4 signalling pathway. This study was first performed in vitro in palmitic acid-induced insulin-resistant HepG2 cells. Various assays, such as FACS, GCMS, qRT-PCR, immunoblot and ChIP-qPCR, were performed to establish the anti-hyperglycaemic role of LyH in vitro. The in vitro results were subsequently confirmed in vivo using a high-fat diet-induced diabetic C57BL/6 mice model. The in vivo study was supported by several experiments, such as examining blood parameters, histopathology, double-immunohistochemistry and ELISA. Finally, the finding was validated by comparing it with a couple of GEO datasets from the NCBI database. This study found that LyH is an excellent choice for regulating blood sugar levels under diabetic conditions without significant harmful side effects. Moreover, LyH showed excellent hepatic glucose uptake activity in an insulin-independent manner. This activity is mainly governed by sugars as its main ingredient. LyH treatment also regulates hepatic lipid homeostasis by maintaining a balance between saturated and unsaturated fatty acids in insulin-resistant HepG2 cells. Further, sugar, when supplemented individually, caused severe inflammation, which was validated through histopathology, ELISA and IHC. Collectively, the findings of this study indicate that Indian LyH provides a better food matrix (the right proportion of sugars and different bioactive compounds), which significantly improves hyperglycemia and inflammation under diabetic conditions by regulating the hepatic ChREBP/Glut4 axis.

A glucose-dependent carbohydrate-signaling gene regulator named Carbohydrate response element binding protein (ChREBP), has recently been discovered as a major metabolic regulator of enzymes involved in the progression of non-alcoholic fatty liver disease (NAFLD) and type-II diabetes mellitus (T2DM). As a result, this research is aimed to identify natural small molecules as drug candidates that target the ChREBP in order to counter aggressive NAFLD and T2DM. A comprehensive in silico drug design strategy was implemented to find possible inhibitors of the targeted protein. A site-specific molecular docking approach was used to screen 20 FDA approved anti-diabetic drugs and 494 phytochemicals from the natural sources against the ChREBP, and the top ten compounds were selected for further studies based on their binding affinities. The ADME and toxicity profiles of the selected ten drug compounds demonstrated their efficacy and safety. The result of the MD simulations of the protein-ligand complex structures indicated their stability and potential activity. A comprehensive data screening process following docking, ADMET properties, and MD simulation approaches, five compounds (dieckol, isocorilagin, stachyurin, stachysetin and thonningianin A) with favorable values against the targeted ChREBP were demonstrated which indicates their strong potential as promising and effective drug candidates for the treatment of NAFLD and T2DM.

De novo lipogenesis (DNL) is a metabolic pathway that converts carbohydrates into fatty acids, primarily occurring in the liver and, to a lesser extent, in adipose tissue. While hepatic DNL is highly responsive to dietary carbohydrate intake and regulated by insulin via transcription factors like SREBP-1c, adipose DNL is more modest and less sensitive to dietary overfeeding. Dysregulated DNL contributes to metabolic disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). Lifestyle interventions, such as physical exercise, ketogenic diets, and time-restricted eating (TRE) offer promising strategies to regulate DNL and improve metabolic health. Physical exercise enhances glucose uptake in muscles, reduces insulin levels, and promotes lipid oxidation, thereby suppressing hepatic DNL. Endurance and resistance training also improve mitochondrial function, further mitigating hepatic triglyceride accumulation. Ketogenic diets shift energy metabolism toward fatty acid oxidation and ketogenesis, lower insulin, and directly downregulate lipogenic enzyme activity in the liver. TRE aligns feeding with circadian rhythms by optimizing AMP-activated protein kinase (AMPK) activation during fasting periods, which suppresses DNL and enhances lipid metabolism. The combined effects of these interventions demonstrate significant potential for improving lipid profiles, reducing hepatic triglycerides, and preventing lipotoxicity. By addressing the distinct roles of the liver and adipose DNL, these strategies target systemic and localized lipid metabolism dysregulation. Although further research is needed to fully understand their long-term impact, these findings highlight the transformative potential of integrating these approaches into clinical practice to manage metabolic disorders and their associated complications.

Important health disparities are observed in the prevalence of obesity and associated non-communicable diseases (NCDs), including type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD) among ethnic groups. Yet, the underlying factors accounting for these disparities remain poorly understood. Fructose has been widely proposed as a potential mediator of these NCDs, given that hepatic fructose catabolism can result in deleterious metabolic effects, including insulin resistance and hepatic steatosis. Moreover, the fermentation of fructose by the gut microbiota can produce metabolites such as ethanol and acetate, both which serve as potential substrates for de novo lipogenesis (DNL) and could therefore contribute to the development of these metabolic conditions. Significant inter-ethnic differences in gut microbiota composition have been observed. Moreover, fructose consumption varies across ethnic groups, and fructose intake has been demonstrated to significantly alter gut microbiota composition, which can influence its fermenting properties and metabolic effects. Therefore, ethnic differences in gut microbiota composition, which may be influenced by variations in fructose consumption, could contribute to the observed health disparities. This review provides an overview of the complex interactions between host and microbial fructose catabolism, the role of ethnicity in shaping these metabolic processes and their impact on host health. Understanding these interactions could provide insights into the mechanisms driving ethnic health disparities to improve personalized nutrition strategies. KEY POINTS: Dietary fructose consumption has increased substantially over recent decades, which has been associated with the rising prevalence of obesity and non-communicable diseases (NCDs) such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease. Pronounced disparities among different ethnic groups in NCD prevalence and dietary fructose consumption underscore the need to elucidate the underlying mechanisms of fructose catabolism and its health effects. Together with the well-known toxic effects of hepatic fructose catabolism, emerging evidence highlights a role for the small intestinal microbiota in fermenting sugars like fructose into various bacterial products with potential deleterious metabolic effects. There are significant ethnic differences in gut microbiota composition that, combined with varying fructose consumption, could mediate the observed health disparities. To comprehensively understand the role of the gut microbiota in mediating fructose-induced adverse metabolic effects, future research should focus on the small intestinal microbiota. Future research on fructose - microbiota - host interactions should account for ethnic differences in dietary habits and microbial composition to elucidate the potential role of the gut microbiota in driving the mentioned health disparities.

Introduction: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) stems from disrupted lipid metabolism in the liver, often linked to obesity, type 2 diabetes, and dyslipidemia. In Mexico, where obesity affects 36.9% of adults, MASLD prevalence has risen, especially with metabolic syndrome affecting 56.31% by 2018. MASLD can progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH), affecting 5.27% globally, leading to severe complications like cirrhosis and hepatocellular carcinoma. Background: Visceral fat distribution varies by gender, impacting MASLD development due to hormonal influences. Insulin resistance plays a central role in MASLD pathogenesis, exacerbated by high-fat diets and specific fatty acids, leading to hepatic steatosis. Lipotoxicity from saturated fatty acids further damages hepatocytes, triggering inflammation and fibrosis progression in MASH. Diagnosing MASLD traditionally involves invasive liver biopsy, but non-invasive methods like ultrasound and transient elastography are preferred due to their safety and availability. These methods detect liver steatosis and fibrosis with reasonable accuracy, offering alternatives to biopsy despite varying sensitivity and specificity. Conclusions: MASLD as a metabolic disorder underscores its impact on public health, necessitating improved awareness and early management strategies to mitigate its progression to severe liver diseases.

Genome-wide association studies identified a 20-Kb region of chromosome 8 (8q24.13) associated with plasma lipids, hepatic steatosis, and risk for coronary artery disease. The region is proximal to TRIB1, and given its well-established role in lipid regulation in animal models, TRIB1 has been proposed to mediate the contribution of the 8q24.13 locus to these traits. This region overlaps a gene encoding the primate-specific long noncoding RNA transcript TRIBAL/TRIB1AL (TRIB1-associated locus), but the contribution of TRIBAL to coronary artery disease risk remains untested.

Using recently available expression quantitative trait loci data and hepatocyte models, we further investigated this locus by Mendelian randomization analysis. Following antisense oligonucleotide targeting of TRIBAL, transcription array, quantitative reverse transcription polymerase chain reaction, and enrichment analyses were performed and effects on apoB and triglyceride secretion were determined.

Mendelian randomization analysis supports a causal relationship between genetically determined hepatic TRIBAL expression and markers of hepatic steatosis and coronary artery disease risk. By contrast, expression data sets did not support expression quantitative trait loci relationships between coronary artery disease-associated variants and TRIB1. TRIBAL suppression reduced the expression of key regulators of triglyceride metabolism and bile acid synthesis. Enrichment analyses identified patterns consistent with impaired metabolic functions, including reduced triglyceride and cholesterol handling ability. Furthermore, TRIBAL suppression was associated with reduced hepatocyte secretion of triglycerides.

This work identifies TRIBAL as a gene bridging the genotype-phenotype relationship at the 8q24.13 locus with effects on genes regulating hepatocyte lipid metabolism and triglyceride secretion.

Type 2 diabetes (T2DM) is one of the major metabolic diseases and poses a serious challenge to human life and global economic development. Jinqi Jiangtang Tablets (JQJT) is effective in ameliorating the effects of T2DM, but the mechanism of JQJT is unclear.

This study integrated metabolomics and transcriptomics to reveal the mechanism by which JQJT improves T2DM.

The T2DM mouse model was established, and the effects of JQJT on improving T2DM were evaluated by determining the levels of blood lipids, fasting blood glucose (FBG), insulin metabolism and hepatic lipid accumulation in mice after JQJT administration for 8 weeks. Serum metabolites were detected using ultra-performance liquid chromatography/quadrupole time-of-flight-tandem mass spectrometry (UPLC-Q-TOF-MS) technology, and mouse liver differential genes were detected using transcriptomic technology. Correlation analysis was used to extract metabolites and RNA with correlations, and potential pathways were enriched and constructed using the common pathway analysis function of MetaboAnalyst 5.0. Finally, the expression of key target proteins and genes was verified by Western blot (WB) and Polymerase Chain Reaction (PCR) to further elucidate the mechanism by which JQJT improves T2DM.

JQJT reduced FBG and lipid levels, improved insulin resistance (IR) and hepatic lipoatrophy in mice. A total of 35 differentially abundant metabolites were identified by metabolomics, and 328 differential genes were detected by transcriptomics. The integrated metabolomics and transcriptomics results suggested that JQJT may ameliorate T2DM mainly by regulating glucose and lipid metabolic pathways. WB and PCR results showed that JQJT regulates the insulin signaling pathway, involved in fatty acid metabolism, glycogen synthesis and catabolism.

JQJT improved IR in T2DM mice by regulating the insulin signaling pathway, improving glycogen synthesis and glycolysis, and increasing hepatic triglyceride and fatty acid metabolism.

Elevated lipid synthesis is one of the best-characterized metabolic alterations in cancer and crucial for membrane expansion. As a key rate-limiting enzyme in de novo fatty acid synthesis, ATP-citrate lyase (ACLY) is frequently up-regulated in tumors and regulated by posttranslational modifications (PTMs). Despite emerging evidence showing O-GlcNAcylation on ACLY, its biological function still remains unknown. Here, we observed a significant upregulation of ACLY O-GlcNAcylation in various types of human tumor cells and tissues and identified S979 as a major O-GlcNAcylation site. Importantly, S979 O-GlcNAcylation is required for substrate CoA binding and crucial for ACLY enzymatic activity. Moreover, it is sensitive to glucose fluctuation and decisive for fatty acid synthesis as well as tumor cell proliferation. In response to EGF stimulation, both S979 O-GlcNAcylation and previously characterized S455 phosphorylation played indispensable role in the regulation of ACLY activity and cell proliferation; however, they functioned independently from each other. In vivo, streptozocin treatment- and EGFR overexpression-induced growth of xenograft tumors was mitigated once S979 was mutated. Collectively, this work helps comprehend how cells interrogate the nutrient enrichment for proliferation and suggests that although mammalian cell proliferation is controlled by mitogen signaling, the ancient nutrition-sensing mechanism is conserved and still efficacious in the cells of multicellular organisms.

Pancreatic cancer is a lethal disease with limited effective treatments. A deeper understanding of its molecular mechanisms is crucial to reduce incidence and mortality. Epidemiological evidence suggests a link between diet and disease risk, though dietary recommendations for at-risk individuals remain debated. Here, we propose that cell-intrinsic nutrient sensing pathways respond to specific diet-derived cues to facilitate oncogenic transformation of pancreatic epithelial cells. This review explores how diet influences pancreatic cancer predisposition through nutrient sensing and downstream consequences for (pre-)cancer cell biology. We also examine experimental evidence connecting specific food intake to pancreatic cancer progression, highlighting nutrient sensing as a promising target for therapeutic development to mitigate disease risk.

Stable isotope studies have shown that hepatic de novo lipogenesis (DNL) plays an important role in the pathogenesis of intrahepatic lipid (IHL) deposition. Furthermore, previous research has demonstrated that fructose 1-phosphate (F1P) not only serves as a substrate for DNL, but also acts as a signalling metabolite that stimulates DNL from glucose. The aim of this study was to elucidate the mediators of F1P-stimulated DNL, with special focus on two key regulators of intrahepatic glucose metabolism, i.e., glucokinase regulatory protein (GKRP) and carbohydrate response element binding protein (ChREBP).

Aldolase B deficient mice (Aldob-/-), characterized by hepatocellular F1P accumulation, enhanced DNL, and hepatic steatosis, were either crossed with GKRP deficient mice (Gckr-/-) or treated with short hairpin RNAs directed against hepatic ChREBP.

Aldob-/- mice showed higher rates of de novo palmitate synthesis from glucose when compared to wildtype mice (p < 0.001). Gckr knockout reduced de novo palmitate synthesis in Aldob-/- mice (p = 0.017), without affecting the hepatic mRNA expression of enzymes involved in DNL. In contrast, hepatic ChREBP knockdown normalized the hepatic mRNA expression levels of enzymes involved in DNL and reduced fractional DNL in Aldob-/- mice (p < 0.05). Of interest, despite downregulation of DNL in response to Gckr and ChREBP attenuation, no reduction in intrahepatic triglyceride levels was observed.

Both GKRP and ChREBP mediate F1P-stimulated DNL in aldolase B deficient mice. Further studies are needed to unravel the role of GKRP and hepatic ChREBP in regulating IHL accumulation in aldolase B deficiency.

The intracellular lipids in muscle cells of farm animals play a crucial role in determining the overall intramuscular fat (IMF) content, which has a positive impact on meat quality. However, the mechanisms underlying the deposition of lipids in muscle cells of farm animals are not yet fully understood. The purpose of this study was to determine the roles of carbohydrate-response element binding protein (ChREBP) and fructose in IMF deposition of chickens. For virus-mediated ChREBP overexpression in tibialis anterior (TA) muscle of chickens, seven 5-d-old male yellow-feather chickens were used. At 10 d after virus injection, the chickens were slaughtered to obtain TA muscles for analysis. For fructose administration trial, sixty 9-wk-old male yellow-feather chickens were randomly divided into 2 groups, with 6 replicates per group and 5 chickens per replicate. The chickens were fed either a basal diet or a basal diet supplemented with 10% fructose (purity ≥ 99%). At 4 wk later, the chickens were slaughtered, and breast and thigh muscles were collected for analysis. The results showed that the skeletal ChREBP mRNA levels were positively associated with IMF content in multiple species, including the chickens, pigs, and mice (P < 0.05). ChREBP overexpression increased lipid accumulation in both muscle cells in vitro and the TA muscles of mice and chickens in vivo (P < 0.05), by activation of the de novo lipogenesis (DNL) pathway. Moreover, activation of ChREBP by dietary fructose administration also resulted in increased IMF content in mice and notably chickens (P < 0.05). Furthermore, the lipidomics analysis revealed that ChREBP activation altered the lipid composition of chicken IMF and tented to improve the flavor profile of the meat. In conclusion, this study found that ChREBP plays a pivotal role in mediating the deposition of fat in chicken muscles in response to fructose-rich diets, which provides a novel strategy for improving meat quality in the livestock industry.

Unlike protein-coding genes, the majority of human long non-coding RNAs (lncRNAs) lack conservation based on their sequences, posing a challenge for investigating their role in a pathophysiological context for clinical translation. This study explores the hypothesis that non-conserved lncRNAs in human and mouse livers may share similar metabolic functions, giving rise to functionally conserved lncRNA metabolic regulators (fcLMRs).

We developed a sequence-independent strategy to select putative fcLMRs, and performed extensive analysis to determine the functional similarities of putative human and mouse LMR pairs (h/mLMRs).

We found that several pairs of putative fcLMRs share similar functions in regulating gene expression. We further demonstrated that a pair of fcLMRs, h/mLMR1, robustly regulated triglyceride levels by modulating the expression of a similar set of lipogenic genes. Mechanistically, h/mLMR1 binds to PABPC1, a regulator of protein translation, via short motifs on either lncRNA with divergent sequences but similar structures. This interaction inhibits protein translation, activating an amino acid-mTOR-SREBP1 axis to regulate lipogenic gene expression. Intriguingly, PABPC1-binding motifs on each lncRNA fully rescued the functions of their corresponding LMRs in the opposite species. Given the elevated expression of h/mLMR1 in humans and mice with hepatic steatosis, the PABPC1-binding motif on hLMR1 emerges as a potential non-conserved human drug target whose functions can be fully validated in a physiologically relevant setting before clinical studies.

Our study supports that fcLMRs represent a novel and prevalent biological phenomenon, and deep phenotyping of genetic mLMR mouse models constitutes a powerful approach to understand the pathophysiological role of lncRNAs in the human liver.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a serious health problem, and recent evidence indicates that gut microbiota plays a key role in its development. It is known that 2-oleoyl glycerol (2-OG) produced by the gut microbiota is associated with hepatic fibrosis, but it is not known whether this metabolite is involved in the development of hepatic steatosis. The aim of this study was to evaluate how a high-fat-sucrose diet (HFS) increases 2-OG production through gut microbiota dysbiosis and to identify whether this metabolite modifies hepatic lipogenesis and mitochondrial activity for the development of hepatic steatosis as well as whether a combination of functional foods can reverse this process. Wistar rats were fed the HFS diet for 7 months. At the end of the study, body composition, biochemical parameters, gut microbiota, protein abundance, lipogenic and antioxidant enzymes, hepatic 2-OG measurement, and mitochondrial function of the rats were evaluated. Also, the effect of the consumption of functional food with an HFS diet was assessed. In humans with MASLD, we analyzed gut microbiota and serum 2-OG. Consumption of the HFS diet in Wistar rats caused oxidative stress, hepatic steatosis, and gut microbiota dysbiosis, decreasing α-diversity and increased Blautia producta abundance, which increased 2-OG. This metabolite increased de novo lipogenesis through ChREBP and SREBP-1. 2-OG significantly increased mitochondrial dysfunction. The addition of functional foods to the diet modified the gut microbiota, reducing Blautia producta and 2-OG levels, leading to a decrease in body weight gain, body fat mass, serum glucose, insulin, cholesterol, triglycerides, fatty liver formation, and increased mitochondrial function. To use 2-OG as a biomarker, this metabolite was measured in healthy subjects or with MASLD, and it was observed that subjects with hepatic steatosis II and III had significantly higher 2-OG than healthy subjects, suggesting that the abundance of this circulating metabolite could be a predictor marker of hepatic steatosis.

Objective: This study compared the ability of Liquorice roots aqueous extract (LRE) and its ingredient, isoliquiritigenin (ISL), in alleviating high-fat diet (HFD)-induced hepatic steatosis and examined if this effect involves activation of AMPK.Materials and methods: Control or HFD-fed rats were treated with the vehicle, LRE (200 mg/kg), or ISL (30 mg/kg) for 8 weeks orally.Results: ISL and LRE reduced HFD-induced hyperglycaemia, improved liver structure, lowered serum and hepatic lipids, and attenuated hepatic oxidative stress and inflammation. In the control and HFD-fed rats, ISL and LRE significantly stimulated the muscular and hepatic mRNA and protein levels of AMPK, improved oral glucose tolerance, reduced hepatic mRNA levels of SREBP1/2, and upregulated hepatic levels of PPARα and Bcl2. These effects were comparable for ISL and LRE and were prevented by co-administration of compound C, an AMPK inhibitor.Discussion and conclusion: ISL and LRE provide an effective theory to alleviate hepatic steatosis through activating AMPK.

The prevalence of obesity-induced non-alcoholic fatty liver disease (NAFLD) and insulin resistance is increasing worldwide. We previously demonstrated that sesaminol increases thermogenesis in adipocytes, improves insulin sensitivity, and mitigates obesity in mice. In this study, we demonstrated that sesaminol increased mitochondrial activity and reduced ROS production in hepatocytes. Therefore, we delve into the metabolic action of sesaminol in obesity-induced NAFLD or metabolic dysfunction-associated liver disease (MAFLD). Here, we report that sesaminol induces OXPHOS proteins and mitochondrial function in vivo. Further, our data suggest that sesaminol administration reduces hepatic triacylglycerol accumulation and LDL-C levels. Prominently, the lipidomics analyses revealed that sesaminol administration decreased the major phospholipids such as PC, PE, PI, CL, and PS to maintain membrane lipid homeostasis in the liver upon HFD challenge. Besides, SML reduced ePC and SM molecular species and increased PA levels in the HFD-fed mice. Also, sesaminol renders anti-inflammatory properties and dampens fibrosis markers in the liver. Remarkably, SML lowers the hepatic levels of ALT and AST enzymes and alleviates NAFLD in diet-induced obese mice. The molecular docking analysis identifies peroxisome proliferator-activated receptors as potential endogenous receptors for sesaminol. Together, our study demonstrates plant lignan sesaminol as a potential small molecule that alters the molecular species of major phospholipids, including sphingomyelin and ether-linked PCs in the liver tissue, improves metabolic parameters, and alleviates obesity-induced fatty liver disease in mice.

This study evaluated if miR-34a/SIRT1 signalling mediates the anti-hepatosteatotic effect of resveratrol (RSV) in high-fat-diet (HFD)-fed rats. Rats were divided into seven groups (n = 6/each) as control, control + miR-34a agomir negative control, HFD, HFD + miR-34a, HFD + RSV, HFD + RSV + Ex-527 (a SIRT1 inhibitor), and HFD + RSV + miR-34a agomir. After 8 weeks, RSV suppressed dyslipidemia, lowered fasting glucose and insulin levels, improved insulin sensitivity, and prevented hepatic lipid accumulation. These effects were associated with hepatic downregulation of SREBP1 and SREBP2, upregulation of PPARα, and acetylation of Nrf2 (activation) and NF-κβ p65 (inhibition). Also, RSV reduced the transcription of miR-34a and increased the nuclear localisation of SIRT1 in the livers, muscles, and adipose tissues of HFD-fed rats. All these effects were prevented by EX-527 and miR-34a agmir. In conclusion, RSV prevents HFD-induced insulin resistance and hepatic steatosis by suppressing miR-34a-induced activation of SIRT1.

The pathophysiology of hepatic steatosis is thoroughly reviewed in this comprehensive report, with particular attention to the complex interactions between inflammatory pathways, insulin resistance, lipid metabolism, metabolic dysregulation, and immunological responses in the liver including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC). The study highlights the role of immune cell regulation in disease progression and explores the potential of immune cell-specific treatments for treating hepatic disorders. The development of liver disorders is significantly influenced by immune cells, including dendritic cells, T cells, and natural killer cells. Clinical investigations show that immune cell-specific treatments can effectively reduce liver fibrosis and inflammation. Future research should focus on finding new immunological targets for therapeutic interventions, as well as addressing the management challenges associated with NAFLD/NASH. Hepatic immune microorganisms also impact liver homeostasis and disorders. Improvements in immune cell regulation and liver transplantation methods give patients hope for better prognoses. Important phases include optimizing the selection of donors for malignancy of the liver, using machine perfusion for organ preservation, and fine-tuning immunosuppressive strategies. For focused treatments in hepatic steatosis, it is imperative to understand the intricate interactions between immune and metabolic variables. Understanding the liver's heterogeneous immune profile, encompassing a range of immune cell subpopulations, is crucial for formulating focused therapeutic interventions. To improve patient care and outcomes in hepatic illnesses, there is an urgent need for further research and innovation. Therefore, to effectively treat hepatic steatosis, it is important to enhance therapeutic techniques and maximize liver transplantation strategies.

The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from "nonalcoholic fatty liver disease" (NAFLD) to "metabolic dysfunction-associated fatty liver disease" (MAFLD) and, finally, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut-liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH.

Sterol regulatory element binding protein (SREBP) 1 is considered to be a crucial regulator for lipid synthesis in vertebrates. However, whether SREBP1 could regulate hepatic gluconeogenesis under high-fat diet (HFD) condition is still unknown, and the underlying mechanism is also unclear.

This study aimed to determine gluconeogenesis-related gene and protein expressions in response to HFD in large yellow croaker and explore the role and mechanism of SREBP1 in regulating the related transcription and signaling.

Croakers (mean weight, 15.61 ± 0.10 g) were fed with diets containing 12% crude lipid [control diet (ND)] or 18% crude lipid (HFD) for 10 weeks. The glucose tolerance, insulin tolerance, hepatic gluconeogenesis-related genes, and proteins expressions were determined. To explore the role of SREBP1 in HFD-induced gluconeogenesis, SREBP1 was inhibited by pharmacologic inhibitor (fatostatin) or genetic knockdown in croaker hepatocytes under palmitic acid (PA) condition. To explore the underlying mechanism, luciferase reporter and chromatin immunoprecipitation assays were conducted in HEK293T cells. Data were analyzed using analysis of variance or Student t test.

Compared with ND, HFD increased the mRNA expressions of gluconeogenesis genes (2.40-fold to 2.60-fold) (P < 0.05) and reduced protein kinase B (AKT) phosphorylation levels (0.28-fold to 0.34-fold) (P < 0.05) in croakers. However, inhibition of SREBP1 by fatostatin addition or SREBP1 knockdown reduced the mRNA expressions of gluconeogenesis genes (P < 0.05) and increased AKT phosphorylation levels (P < 0.05) in hepatocytes, compared with that by PA treatment. Moreover, fatostatin addition or SREBP1 knockdown also increased the mRNA expressions of irs1 (P < 0.05) and reduced serine phosphorylation of IRS1 (P < 0.05). Furthermore, SREBP1 inhibited IRS1 transcriptions by binding to its promoter and induced IRS1 serine phosphorylation by activating diacylglycerol-protein kinase Cε signaling.

This study reveals the role of SREBP1 in hepatic gluconeogenesis under HFD condition in croakers, which may provide a potential strategy for improving HFD-induced glucose intolerance.

Common variants of the max-like protein X (MLX)-interacting protein-like (MLXIPL) gene, encoding the transcription factor carbohydrate-responsive element-binding protein, have been shown to be associated with plasma triglyceride levels. However, the role of these variants in steatotic liver disease (SLD) is unclear.

We used a genome-first approach to analyze a variety of metabolic phenotypes and clinical outcomes associated with a common missense variant in MLXIPL, Gln241His, in 2 large biobanks: the UK Biobank and the Penn Medicine Biobank.

Carriers of MLXIPL Gln241His were associated with significantly lower serum levels of triglycerides, apolipoprotein-B, gamma-glutamyl transferase, and alkaline phosphatase. Additionally, MLXIPL Gln241His carriers were associated with significantly higher serum levels of HDL cholesterol and alanine aminotransferase. Carriers homozygous for MLXIPL Gln241His showed a higher risk of SLD in 2 unrelated cohorts. Carriers of MLXIPL Gln241His were especially more likely to be diagnosed with SLD if they were female, obese, and/or also carried the PNPLA3 I148M variant. Furthermore, the heterozygous carriage of MLXIPL Gln241His was associated with significantly higher all-cause, liver-related, and cardiovascular mortality rates. Nuclear magnetic resonance metabolomics data indicated that carriage of MLXIPL Gln241His was significantly associated with lower serum levels of VLDL and increased serum levels of HDL cholesterol.

Analyses of the MLXIPL Gln241His polymorphism showed a significant association with a higher risk of SLD diagnosis and elevated serum alanine aminotransferase as well as significantly lower serum triglycerides and apolipoprotein-B levels. MLXIPL might, therefore, be a potential pharmacological target for the treatment of SLD and hyperlipidemia, notably for patients at risk. More mechanistic studies are needed to better understand the role of MLXIPL Gln241His on lipid metabolism and steatosis development.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease that affects over 30% of the world's population. For decades, the heterogeneity of non-alcoholic fatty liver disease (NAFLD) has impeded our understanding of the disease mechanism and the development of effective medications. However, a recent change in the nomenclature from NAFLD to MASLD emphasizes the critical role of systemic metabolic dysfunction in the pathophysiology of this disease and therefore promotes the progress in the pharmaceutical treatment of MASLD. In this review, we focus on the mechanism underlying the abnormality of hepatic lipid metabolism in patients with MASLD, and summarize the latest progress in the therapeutic medications of MASLD that target metabolic disorders.

Insulin is a polypeptide hormone synthesized and secreted by pancreatic β-cells. It plays an important role as a metabolic hormone. Insulin influences the metabolism of glucose, regulating plasma glucose levels and stimulating glucose storage in organs such as the liver, muscles and adipose tissue. It is involved in fat metabolism, increasing the storage of triglycerides and decreasing lipolysis. Ketone body metabolism also depends on insulin action, as insulin reduces ketone body concentrations and influences protein metabolism. It increases nitrogen retention, facilitates the transport of amino acids into cells and increases the synthesis of proteins. Insulin also inhibits protein breakdown and is involved in cellular growth and proliferation. On the other hand, defects in the intracellular signaling pathways of insulin may cause several disturbances in human metabolism, resulting in several chronic diseases. Insulin resistance, also known as impaired insulin sensitivity, is due to the decreased reaction of insulin signaling for glucose levels, seen when glucose use in response to an adequate concentration of insulin is impaired. Insulin resistance may cause, for example, increased plasma insulin levels. That state, called hyperinsulinemia, impairs metabolic processes and is observed in patients with type 2 diabetes mellitus and obesity. Hyperinsulinemia may increase the risk of initiation, progression and metastasis of several cancers and may cause poor cancer outcomes. Insulin resistance is a health problem worldwide; therefore, mechanisms of insulin resistance, causes and types of insulin resistance and strategies against insulin resistance are described in this review. Attention is also paid to factors that are associated with the development of insulin resistance, the main and characteristic symptoms of particular syndromes, plus other aspects of severe insulin resistance. This review mainly focuses on the description and analysis of changes in cells due to insulin resistance.

Glucose is a sugar crucial for human health since it participates in many biochemical reactions. It produces adenosine 5'-triphosphate (ATP) and nucleosides through glucose metabolic and pentose phosphate pathways. These processes require many transporter proteins to assist in transferring glucose across cells, and the most notable ones are glucose transporter-2 (GLUT-2) and sodium/glucose cotransporter 1 (SGLT1). Glucose enters small intestinal epithelial cells from the intestinal lumen by crossing the brush boundary membrane via the SGLT1 cotransporter. It exits the cells by traversing the basolateral membrane through the activity of the GLUT-2 transporter, supplying energy throughout the body. Dysregulation of these glucose transporters is involved in the pathogenesis of several metabolic diseases, such as diabetes. Natural loss of GLUT-2 or its downregulation causes abnormal blood glucose concentrations in the body, such as fasting hypoglycemia and glucose tolerance. Therefore, understanding GLUT-2 physiology is necessary for exploring the mechanisms of diabetes and targeted treatment development. This article reviews how the apical GLUT-2 transporter maintains normal physiological functions of the human body and the adaptive changes this transporter produces under pathological conditions such as diabetes.

The quality of drinks affects the functioning of the liver. In recent decades, the variety of high-calorie and sweet drinks has increased. The objective of this study was to explore the association between Healthy Beverage Index (HBI) and the risk of nonalcoholic fatty liver disease (NAFLD) among adults. We included 6,276 participants aged 35 to 65 from the Ravansar Non-Communicable Disease (RaNCD) cohort study at baseline. NAFLD is defined based on the fatty liver index (FLI), calculated using anthropometric measurements and non-invasive markers. The HBI was developed using a combination of water, low-fat milk, 100% fruit juice, sugar-sweetened beverages, met fluid requirement and % energy from beverages. Logistic and linear regression models were employed to investigate the associations of the HBI and high FLI. The average FLI was significantly lower in the first tertile of HBI compared to the third tertile (47.83 vs. 45.77; P = 0.001). After adjusting for confounding variables, the odds of high FLI decreased by 28% (OR 0.72, 95% CI 0.63, 0.82) in the second tertile of HBI and by 21% in the third tertile (OR 0.79, 95% CI 0.70, 0.91). There was no correlation between gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and aspartate transaminase (AST) levels with HBI. The study findings indicate an inverse association between high FLI and HBI. Therefore, it is recommended to consume healthy beverages and without added sugar. However, additional longitudinal studies are required to examine the association between beverage consumption and the development of NAFLD.

Increased de novo lipogenesis (DNL) in white adipose tissue is associated with insulin sensitivity. Under both Normal-Chow-Diet and High-Fat-Diet, mice expressing a kinase inactive Cyclin-dependent kinase 6 (Cdk6) allele (K43M) display an increase in DNL in visceral white adipose tissues (VAT) as compared to wild type mice (WT), accompanied by markedly increased lipogenic transcriptional factor Carbohydrate-responsive element-binding proteins (CHREBP) and lipogenic enzymes in VAT but not in the liver. Treatment of WT mice under HFD with a CDK6 inhibitor recapitulates the phenotypes observed in K43M mice. Mechanistically, CDK6 phosphorylates AMP-activated protein kinase, leading to phosphorylation and inactivation of acetyl-CoA carboxylase, a key enzyme in DNL. CDK6 also phosphorylates CHREBP thus preventing its entry into the nucleus. Ablation of runt related transcription factor 1 in K43M mature adipocytes reverses most of the phenotypes observed in K43M mice. These results demonstrate a role of CDK6 in DNL and a strategy to alleviate metabolic syndromes.

Fibrosis, characterized by excessive extracellular matrix accumulation, disrupts normal tissue architecture, causes organ dysfunction, and contributes to numerous chronic diseases. This review focuses on Krüppel-like factor 10 (KLF10), a transcription factor significantly induced by transforming growth factor-β (TGF-β), and its role in fibrosis pathogenesis and progression across various tissues. KLF10, initially identified as TGF-β-inducible early gene-1 (TIEG1), is involved in key biological processes including cell proliferation, differentiation, apoptosis, and immune responses. Our analysis investigated KLF10 gene and protein structures, interaction partners, and context-dependent functions in fibrotic diseases. This review highlights recent findings that underscore KLF10 interaction with pivotal signaling pathways, such as TGF-β, and the modulation of gene expression in fibrotic tissues. We examined the dual role of KLF10 in promoting and inhibiting fibrosis depending on tissue type and fibrotic context. This review also discusses the therapeutic potential of targeting KLF10 in fibrotic diseases, based on its regulatory role in key pathogenic mechanisms. By consolidating current research, this review aims to enhance the understanding of the multifaceted role of KLF10 in fibrosis and stimulate further research into its potential as a therapeutic target in combating fibrotic diseases.

Metabolic-associated steatotic liver disease (MASLD) is a cluster of pathological conditions primarily developed due to the accumulation of ectopic fat in the hepatocytes. During the severe form of the disease, i.e., metabolic-associated steatohepatitis (MASH), accumulated lipids promote lipotoxicity, resulting in cellular inflammation, oxidative stress, and hepatocellular ballooning. If left untreated, the advanced form of the disease progresses to fibrosis of the tissue, resulting in irreversible hepatic cirrhosis or the development of hepatocellular carcinoma. Although numerous mechanisms have been identified as significant contributors to the development and advancement of MASLD, altered lipid metabolism continues to stand out as a major factor contributing to the disease. This paper briefly discusses the dysregulation in lipid metabolism during various stages of MASLD.

Steatosis and inflammation are the hallmarks of nonalcoholic steatohepatitis (NASH). Rotundic acid (RA) is among the key triterpenes of Ilicis Rotundae Cortex and has exhibited multipronged effects in terms of lowering the lipid content and alleviating inflammation. The study objective is to systematically evaluate the potential mechanisms through which RA affects the development and progression of NASH.

Transcriptomic and proteomic analyses of primary hepatocytes isolated from the control, high-fat diet-induced NASH, and RA treatment groups were performed through Gene Ontology analysis and pathway enrichment. Hub genes were identified through network analysis. Integrative analysis revealed key RA-regulated pathways, which were verified by gene and protein expression studies and cell assays.

Hub genes were identified and enriched in the Toll-like receptor 4 (TLR4)/activator protein-1 (AP1) signaling pathway and glycolysis pathway. RA reversed glycolysis and attenuated the TLR4/AP1 pathway, thereby reducing lipid accumulation and inflammation. Additionally, lactate release in L-02 cells increased with NaAsO2-treated and significantly decreased with RA treatment, thus revealing that RA had a major impact on glycolysis.

RA is effective in lowering the lipid content and reducing inflammation in mice with NASH by ameliorating glycolysis and TLR4/AP1 pathways, which contributes to the existing knowledge and potentially sheds light on the development of therapeutic interventions for patients with NASH.

Insulin-sensitive lipogenesis dominates the body lipid deposition; however, nonalcoholic fatty liver disease (NAFLD) develops in the insulin-resistant state. The regulation mechanism of insulin resistance-driven NAFLD remains elusive. Using zebrafish model of insulin resistance (ZIR, insrb-/-) and mouse hepatocytes (NCTC 1469), we explored the regulation mechanism of insulin resistance-driven hepatic lipid deposition under the stimulation of carbohydrate diet (CHD). In ZIR model, insulin resistance induced hyperlipidemia and elevated hepatic lipid deposition via elevating the gene/protein expressions of lipogenic enzymes, that was activated by carbohydrate response element binding protein (ChREBP), rather than sterol regulatory element binding proteins 1c (SREBP-1c). The metabolomic analysis in zebrafish and silencing of chrebp in mouse hepatocytes revealed that the increased hepatic frucotose-6-phosphate (F6P) and glucose-6-phosphate (G6P) promoted the ChREBP-mediated lipid deposition. We further identified that F6P alone was sufficient to activate ChREBP-mediated lipid deposition by a SREBP-1c-independent manner. Moreover, we clarified the suppressed hepatic phosphofructokinase/glucose-6-phosphatase functions and the normal glucokinase function preserved by glucose transporter 2 (GLUT2) manipulated the increased F6P/G6P content in ZIR. In conclusion, the present study revealed that insulin resistance promoted hepatic lipid deposition via the F6P/G6P-mediated ChREBP activation. Our findings deciphered the main regulation pathway for the liver lipid deposition in the insulin-resistant state and identified F6P as a new potential regulator for ChREBP.

Imbalance in hepatic lipid metabolism can lead to an abnormal triglycerides deposition in the hepatocytes which can cause non-alcoholic fatty liver disease (NAFLD). Four main mechanisms responsible for regulating hepatic lipid metabolism are fatty acid uptake, de novo lipogenesis, lipolysis and fatty acid oxidation. Controlling the expression of transcription factors at molecular level plays a crucial role in NAFLD management. This paper reviews various medicinal plants and their bioactive compounds emphasising mechanisms involved in hepatic lipid metabolism, other important NAFLD pathological features, and their promising roles in managing NAFLD through regulating key transcription factors. Although there are many medicinal plants popularly investigated for NAFLD treatment, there is still little information and scientific evidence available and there has been no research on clinical trials scrutinised on this matter. This review also aims to provide molecular information of medicinal plants in NALFD treatment that might have potentials for future scientifically controlled studies.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is nowadays considered the liver manifestation of metabolic syndrome. Its prevalence is increasing worldwide in parallel to the epidemic of diabetes and obesity. MAFLD includes a wide spectrum of liver injury including simple steatosis and non-alcoholic steatohepatitis (NASH) that may lead to serious complications such as liver cirrhosis and liver cancer. The complexity of its pathophysiology and the intricate mechanisms underlying disease progression explains the huge variety of molecules targeting diverse biological mechanisms that have been tested in preclinical and clinical settings in the last two decades. Thanks to the large number of clinical trials of the last few years, most of them still ongoing, the pharmacotherapy scenario of MAFLD is rapidly evolving. The three major components of MAFLD, steatosis, inflammation, and fibrosis seem to be safely targeted with different agents at least in a large proportion of patients. Likely, in the next few years more than one drug will be approved for the treatment of MAFLD at different disease stages. The aim of this review is to synthesize the characteristics and the results of the most advanced clinical trials for the treatment of NASH to evaluate the recent advances of pharmacotherapy in this disease.

Nonalcoholic fatty liver disease (NAFLD) is a progressive condition that encompasses a spectrum of liver disorders, beginning with the simple steatosis, progressing to nonalcoholic steatohepatitis (NASH), and possibly leading to more severe diseases, including liver cirrhosis and hepatocellular carcinoma (HCC). In recent years, the prevalence of NAFLD has increased due to a shift towards energy-dense dietary patterns and a sedentary lifestyle. NAFLD is also strongly associated with metabolic disorders such as obesity and hyperlipidemia. The progression of NAFLD could be influenced by a variety of factors, such as diet, genetic factors, and even epigenetic factors. In contrast to genetic factors, epigenetic factors, including histone modifications, exhibit dynamic and reversible features. Therefore, the epigenetic regulation of the initiation and progression of NAFLD is one of the directions under intensive investigation in terms of pathogenic mechanisms and possible therapeutic interventions. This review aims to discuss the possible mechanisms and the crucial role of histone modifications in the framework of epigenetic regulation in NAFLD, which may provide potential therapeutic targets and a scientific basis for the treatment of NAFLD.

Feed efficiency is a major constraint in the beef industry and has a significant negative correlation with residual feed intake (RFI). RFI is widely used as a measure of feed efficiency in beef cattle and is independent of economic traits such as body weight and average daily gain. However, key traits with commonality or specificity among beef cattle breeds at the same level of RFI have not been reported. Accordingly, the present study hypothesized that signatures associated with feed efficiency would have commonality or specificity in the liver of cattle breeds at the same RFI level. By comparing and integrating liver transcriptome data, we investigated the critical signatures closely associated with RFI in beef cattle using weighted co-expression network analysis, consensus module analysis, functional enrichment analysis and protein network interaction analysis. The results showed that the consensus modules in Angus and Charolais cattle were negatively correlated, and four (turquoise, red, tan, yellow) were significantly positively correlated in Angus liver, while (turquoise, red) were significantly negatively correlated in Charolais liver. These consensus modules were found to be primarily involved in biological processes such as substance metabolism, energy metabolism and gene transcription, which may be one of the possible explanations for the difference in feed efficiency between the two beef breeds. This research also identified five key candidate genes, PLA2G12B, LCAT, MTTP, LCAT, ABCA1 and FADS1, which are closely associated with hepatic lipid metabolism. The present study has identified some modules, genes and pathways that may be the major contributors to the variation in feed efficiency among different cattle breeds, providing a new perspective on the molecular mechanisms of feed efficiency in beef cattle and a research basis for investigating molecular markers associated with feed efficiency in beef cattle.