Computer‐Aided Functional Oligosaccharide Screening and the Regulatory Role in Lipid Metabolism

Akt2 Is Required for Hepatic Lipid Accumulation in Models of Insulin Resistance

Metabolic associated fatty liver disease (MAFLD) is associated with obesity, type 2 diabetes mellitus, and other metabolic syndromes. Farnesoid X receptor (FXR, NR1H4) plays a prominent role in hepatic lipid metabolism. This study combined the expression of liver genes in FXR knockout (KO) mice and MAFLD patients to identify new pathogenic pathways for MAFLD based on genome-wide transcriptional profiling. In addition, the roles of new target genes in the MAFLD pathogenic pathway were also explored. Two groups of differentially expressed genes were obtained from FXR-KO mice and MAFLD patients by transcriptional analysis of liver tissue samples. The similarities and differences between the two groups of differentially expressed genes were analyzed to identify novel pathogenic pathways and target genes. After the integration analysis of differentially expressed genes, we identified 134 overlapping genes, many of which have been reported to play an important role in lipid metabolism. Our unique analysis method of comparing differential gene expression between FXR-KO mice and patients with MAFLD is useful to identify target genes and pathways that may be strongly implicated in the pathogenesis of MAFLD. The overlapping genes with high specificity were screened using the Gene Expression Omnibus (GEO) database. Through comparison and analysis with the GEO database, we determined that BHMT2 and PKLR could be highly correlated with MAFLD. Clinical data analysis and RNA interference testing in vitro confirmed that BHMT2 may a new regulator of lipid metabolism in MAFLD pathogenesis. These results may provide new ideas for understanding the pathogenesis of MAFLD and thus provide new targets for the treatment of MAFLD.

Screening for Nonalcoholic Fatty Liver Disease in Persons with Type 2 Diabetes in the United States Is Cost-effective: A Comprehensive Cost-Utility Analysis

Nuclear transcription factors and lipid homeostasis in liver

Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (ShpHep−/−) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. ShpHep−/− mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of ShpHep−/− mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the ShpHep−/− mice. In contrast, livers of ShpHep−/− mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development. Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (ShpHep−/−) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. ShpHep−/− mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of ShpHep−/− mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the ShpHep−/− mice. In contrast, livers of ShpHep−/− mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and, indeed, worldwide. It has become a global public health issue. In the United States, the prevalence in the general population is estimated at approximately 20%, while that in the morbidly obese population at approximately 75-92% and in the pediatric population at approximately 13-14%. The progressive form of NAFLD, nonalcoholic steatohepatitis, is estimated at approximately 3-5%, with approximately 3-5% of these having progressed to cirrhosis. Thus, the numbers of individuals at risk for end-stage liver disease and development of primary liver cancer is large. NAFLD is an independent risk factor for cardiovascular disease, leads to increased all-cause mortality, and to increased liver-related mortality. This review focuses on recent advances in our understanding of the NAFLD disease spectrum, including etiology, diagnosis, treatment, and genetic and environmental risk factors and suggests future directions for research in this important area.

Fibroblast growth factor 21 as a biomarker for NAFLD: Integrating pathobiology into clinical practice

ABSTRACTPeroxisome proliferator‐activated receptor gamma (PPARγ) is a critical therapeutic target for metabolic disorders like non‐alcoholic fatty liver disease (NAFLD). However, PPARγ full agonists such as rosiglitazone (ROSI) exhibit limited efficacy and off‐target effects. Intriguingly, transcriptomic analyses revealed dynamic PPARγ expression during NAFLD progression—compensatory upregulation in early stages and downregulation in advanced disease—highlighting the need for novel modulators. This study investigates the therapeutic potential of stachyose (STA), a natural bioactive compound, in NAFLD and its mechanism of action via PPARγ modulation. Using structure‐based virtual screening of 4531 natural compounds, STA was identified as a PPARγ‐targeted ligand, validated by surface plasmon resonance and molecular docking. Network pharmacology and functional enrichment analyses elucidated STA's multi‐target effects. In vitro and in vivo models assessed STA's impacts on lipid metabolism, inflammation, and insulin resistance. Molecular dynamics simulations and post‐translational modification studies clarified STA‐PPARγ interactions. STA outperformed ROSI in mitigating hepatic lipid accumulation, inflammation, and insulin resistance in both models. STA bound stably to PPARγ via residues GLU259, GLY284, PHE287, ILE341, and LEU270, with reduced PPARγ acetylation mediated by SIRT1 activation. Unlike ROSI, STA preserved PPARγ activity without inhibiting phosphorylation at Ser273, suggesting a distinct mechanism of action. STA emerges as a partial PPARγ agonist with superior efficacy and safety profiles compared to ROSI. Its dual role in enhancing fatty acid oxidation and suppressing lipogenesis, coupled with SIRT1‐dependent deacetylation of PPARγ, positions STA as a promising candidate for NAFLD therapy. This study provides a mechanistic foundation for developing PPARγ‐targeted interventions with reduced side effects.

The prevalence of non-alcoholic fatty liver disease (NAFLD), a condition characterized by an excessive accumulation of triglycerides (TGs) in hepatocytes, has dramatically increased globally during recent decades. MicroRNAs (miRs) have been suggested to play crucial roles in many complex diseases and lipid metabolism. Our results indicated that miR199a-5p was remarkably upregulated in free fatty acid (FA)-treated hepatocytes. To investigate the role of miR199a-5p in the pathogenesis of fatty liver and the potential mechanism by which miR199a-5p regulates NAFLD, we first transfected two hepatocyte cell lines, HepG2 and AML12 cells, with agomiR199a-5p or antagomiR199a-5p. Our results indicated that miR199a-5p overexpression exacerbated deposition of FA and inhibited ATP levels and mitochondrial DNA (mtDNA) contents. Consistently, suppression of miR199a-5p partially alleviated deposition of FA and increased ATP levels and mtDNA contents. Moreover, miR199a-5p suppressed the expression of mitochondrial FA β-oxidation-related genes through inhibition of caveolin1 (CAV1) and the related peroxisome proliferator-activated receptor alpha (PPARα) pathway. Furthermore, suppression of CAV1 gene expression by CAV1 siRNA inhibited the PPARα signalling pathway. Finally, we examined the expression of miR199a-5p in liver samples derived from mice fed a high-fat diet, db/db mice, ob/ob mice and NAFLD patients, and found that miR199a-5p was upregulated while CAV1 and PPARA were downregulated in these systems, which was strongly indicative of the essential role of miR199a-5p in NAFLD. In summary, miR199a-5p plays a vital role in lipid metabolism, mitochondrial activity and mitochondrial β-oxidation in liver. Upregulated miR199a-5p in hepatocytes may contribute to impaired FA β-oxidation in mitochondria and aberrant lipid deposits, probably via CAV1 and the PPARα pathway.

These recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic [Medline search up to June 2011]; (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines; (3) guideline policies of the three societies approving this document; and (4) the experience of the authors and independent reviewers with regards to NAFLD. Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B) or low-quality (C). This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.

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

Aim of review. To consider different treatment options for dyslipidemia in non-alcoholic fatty liver disease (NAFLD). Summary. NAFLD occurs in 20-30% of adult population. In the Russian Federation its rate is estimated as high as 37,1%. In the most of NAFLD cases severe disorder of lipid metabolism takes place. In large clinical trials it was demonstrated that the dyslipidemia significantly increases cardiovascular risks and worsens life expectancy in these patients. In the present overview treatment options of several therapeutic agents for dyslipidemia treatment at NAFLD are discussed: phenofibrate, omega-3 polyunsaturated fatty acids (omega-3-PUFAs) and S-adenosylmethionine (SAM). Results of numerous experiments and several clinical trials form the basis for phenofibrate administration for NAFLD patients. In animal experiments the positive role of phenofibrate as PPARα agonist was demonstrated (Peroxisome proliferator activated receptor alpha) for NAFLD prevention and treatment. Results of several studies published at the moment demonstrate that at NAFLD lipid metabolism markers, and serum transaminase levels normalize, sensitivity to insulin increases, the liver histology pattern improves at phenofibrate treatment. Specification of efficacy and safety of application of the drug requires more large-scale clinical studies. Omega-3-PUFAs is one more option in the lipid metabolism disorders treatment in this group of patients. These substances play important role in lipid metabolism regulating expression of the genes (including PPARα) involved in lipid and glucose metabolism. Available clinical trials demonstrate high therapeutical effect of these agents at NAFLD. In the review results of the experimental studies investigating the role of SAM in NAFLD pathogenesis and disorders of lipid metabolism is presented. Conclusion. Now data on a pathogenesis of lipid metabolism disorders at NAFLD are accumulated. The bulk of experimental data and series of clinical trials allow to assume positive affect of such drugs as phenofibrate, omega-3-PUFA and SAMe for treatment of dyslipidemia. Further high-grade studies in this area is necessary.

Epidemiology of non-alcoholic fatty liver disease in China

Biomarkers in Fatty Liver Disease—Here is the Skinny

Reduction of Hepatosteatosis and Lipid Levels by an Adipose Differentiation-Related Protein Antisense Oligonucleotide