Suppression of hepatic steatosis in non-alcoholic steatohepatitis model by modified Xiaoyao San formula: Evidence, mechanisms and perspective.

In this letter, we comment on a recent publication by Mei et al , in the World Journal of Hepatology , investigating the hepatoprotective effects of the modified Xiaoyao San (MXS) formula in a male rat model of non-alcoholic steatohepatitis (NASH). The authors found that MXS treatment mitigated hepatic steatosis and inflammation in the NASH model, as evidenced by the reduction in lipid droplets (LDs), fibrosis markers and lipogenic factors. Interestingly, these hepatoprotective effects were associated with androgen upregulation (based on metabolomics analysis of male steroid hormone metabolites), adenosine 5’-monophosphate-activated protein kinase (AMPK) activation, and restoration of phosphatase and tensin homolog (PTEN) expression. However, the authors did not clearly discuss the relationships between MXS-induced hepatic steatosis reduction in the NASH model, and androgen upregulation, AMPK activation, and restoration of PTEN expression. This editorial emphasizes the reported mechanisms and explains how they act or interact with each other to reduce hepatic steatosis and inflammation in the NASH model. As a perspective, we propose additional mechanisms (such as autophagy/lipophagy activation in hepatocytes) for the clearance of LDs and suppression of hepatic steatosis by MXS in the NASH model. A proper understanding of the mechanisms of MXS-induced reduction of hepatic steatosis might help in the treatment of NASH and related diseases.

Insulin Resistance: Cause or Consequence of Nonalcoholic Steatohepatitis?

AMPK activation by AICAR reduces diet induced fatty liver in C57BL/6 mice

Oxymatrine reduces hepatic lipid synthesis in rat model of nonalcoholic steatohepatitis by regulating Sirt1/AMPK and LXR/Plin2/SREBP-1c pathways.

The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Adenosine monophosphate-activated protein kinase (AMPK) activation is beneficial for NAFLD treatment. Recent studies show the excessive fission of mitochondria during NAFLD progression, so targeting mitochondria dynamics may be a possible target for NAFLD. Still, little is known about whether AMPK regulates mitochondrial dynamics in hepar. This study investigated whether AMPK activation alleviates hepatic steatosis by regulating mitochondrial dynamics mediated by GTPase dynamin-related protein 1 (Drp1). Human hepatocyte line L-02 cells were cultured and subjected to palmitic acid (PA) treatment for 24 h to establish a hepatic steatosis model in vitro, which was pre-treated with different tool drugs. Hepatocyte function, hepatocyte lipid content, mitochondrial reactive oxygen species (ROS) production, and mitochondrial membrane potential (MMP) were examined. The expression levels of genes and proteins associated with mitochondrial dynamics were assessed using reverse transcription-quantitative PCR and western blotting. The results indicated that 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an AMPK activator, improved hepatocyte function, as demonstrated by decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity (P<0.05 or P<0.01). In addition, AICAR decreased total cholesterol (TC) and triglyceride (TG) content and lipid deposition in hepatocytes (P<0.01); decreased ROS production; improved MMP (P<0.01); reduced fission-1 (Fis1) and mitochondrial fission factor (Mff) mRNA expression; and downregulated p-Drp1 (Ser 616) protein expression. In contrast, AICAR increased mitochondrial fusion factor mitofusin-1 (Mfn1) and mitofusin-2 (Mfn2) mRNA expression and upregulated p-Drp1 (Ser 637) protein expression. Mdivi-1, a Drp-1 inhibitor, was used to confirm whether mitochondrial dynamics regulated by Drp1-mediated the role of AICAR. Similar to AICAR, Mdivi-1 improved hepatocyte function and MMP significantly, decreased ROS production and lipid deposition, downregulated Fis1 and Mff mRNA expression, downregulated p-Drp1 (Ser 616) protein expression, and enhanced Mfn1 and Mfn2 mRNA and p-Drp1 (Ser 637) protein expression. However, Compound C, an AMPKspecific inhibitor, had less impact on the protective effect of Mdivi-1. The results demonstrated that AMPK activation has a protective effect on hepatic steatosis in vitro, largely dependent on the inhibition of Drp1-mediated mitochondrial fission.

Pentoxifylline: not just for alcoholic hepatitis anymore?

Non-alcoholic fatty liver disease (NAFLD), a growing health issue around the world, is defined as the presence of steatosis in the liver without any other detectable byproducts such as alcohol consumption, which includes a wide spectrum of pathologies, such as steatohepatitis, cirrhosis, and hepatocellular carcinoma. A growing body of evidence indicates that the reduction in the 5' adenosine monophosphate-activated protein kinase (AMPK) activity, which could be activated by the consumption of the drugs, hormones, cytokines, and dietary restriction, is related to some metabolic disorders such as obesity, diabetes, PCOS, and NAFLD. Vanillic acid (VA), as an anti-inflammatory, anti-oxidative, anti-angiogenic and anti-metastatic factor, has protective effects on the liver as in two animal models of liver damage, it reduces serum levels of transaminases, inflammatory cytokines, and the accumulation of collagen in the liver and also prevents liver fibrosis. Besides, it decreases body and adipose tissue weight in a mice model of obesity and, similar to the liver tissue, diminishes adipogenesis through the activation of AMPK. It has been reported that VA can target almost all of the metabolic abnormalities of NAFLD, such as hepatic steatosis, inflammation, and hepatic injury, at least partially through the activation of AMPK. Therefore, in this review, we will discuss the possible and hypothetical roles of VA in NAFLD, with a special focus on AMPK.

Hindbrain adenosine 5'-monophosphate-activated protein kinase (AMPK) activation alters hypothalamic neuronal genomic activity in an estradiol (E)-dependent manner. This study examines the premise that E regulates metabolic effector neuron reactivity to hindbrain AMPK. Paraventricular (PVH), arcuate (ARH), and ventromedial (VMH) nuclei were micropunched from brains of E- or oil (O)-implanted ovariectomized female rats that had been injected, into the fourth ventricle, with the AMPK activator 5-aminoimidazole-4-carboxamide-riboside (AICAR; A) or saline (S) and analyzed by quantitative polymerase chain reaction and Western blotting for neurotransmitter mRNA and protein expression. PVH corticotrophin-releasing hormone gene and protein profiles were decreased in O/A and E/A animals. ARH pro-opiomelanocortin (POMC) mRNA and protein were both elevated in O/A but were diminished or unchanged, respectively, in E/A animals; ARH neuropeptide Y (NPY) transcription was inhibited in O/A and E/A animals, but neuropeptide content was augmented in E/A only. VMH SF-1 mRNA and protein were reduced in O and E animals. AICAR did not alter AMPK protein in any structure but elevated PVH (↑E), did not alter ARH, and decreased VMH (↓O,↓E) pAMPK. Results demonstrate hypothalamic metabolic neurotransmitter and AMPK reactivity to hindbrain AMPK activation, including E-dependent adjustments in POMC and NPY transcription and protein expression. Dissimilar POMC (↑O vs. ↔E) and NPY (↓O vs. ↑E) neuropeptide responses to caudal fourth ventricle AICAR indicate E regulation of hindbrain AMPK signaling and/or target receptivity, implying that ARH-controlled metabolic responses may differ in the presence vs. absence of E. Evidence for variable changes in hypothalamic AMPK activity resulting from hindbrain sensor manipulation suggests that individual (or region-based groups of) AMPK-expressing neuron populations are uniquely impacted by hindbrain AMPK.

OP79 ADIPOKINES MEDIATE THE RELATIONSHIPS BETWEEN ABDOMINAL ADIPOSITY AND INSULIN RESISTANCE IN ASIAN ETHNIC GROUPS: SINGAPORE ADULT METABOLISM STUDY (SAMS)

nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to steatohepatitis (NASH), increasing fibrosis and eventually, cirrhosis ([22][1]). Importantly, NASH accompanied by fibrosis and severe inflammation is the most relevant predictor for disease progression

Non‐alcoholic steatohepatitis (NASH) is becoming the most prevalent metabolic liver disorder and is a serious global health burden. Farnesoid X receptor (FXR) agonists are in late stage clinical development to counter the disease and promise therapeutic efficacy. However, the multi‐factorial nature of NASH pathogenesis and progression indicate the need for a therapeutic approach that will target multiple pathophysiological aspects of NASH. We have developed a dual FXR agonist/soluble epoxide hydrolase (sEH) inhibitor (FXRA/sEHI) and investigated its ability to prevent NASH in toxin‐ and diet‐induced mouse NASH models. Toxin‐induced NASH was achieved in male C57BL/6 mice by injecting 200 μg streptozotocin (STZ) solution two days after birth and feeding a high‐fat diet after 4 weeks of age. Diet‐induced NASH was carried out in adult (8–12 weeks old) male C57BL/6J mice fed a methionine‐choline deficient diet (MCD; D518810) and was compared to mice fed a composition‐matched methionine‐choline replete control diet (D518754) for 4 weeks. In toxin‐induced NASH model, mice were orally treated with vehicle or FXRA/sEHI (10 mg/kg, thrice daily) or an FXR agonist obeticholic acid (OCA, 10 mg/kg, once daily) for 4 weeks. The mice from diet‐induced NASH model treated with FXRA/sEHI (10 mg/kg/d) or vehicle given in drinking water for 4 weeks. At the end of the 4‐week treatment period, blood was collected for biochemical analysis, liver tissue was collected for mRNA expression and histopathological analysis. Mice of the toxin‐induced NASH model had higher liver enzyme, hyperlipidemia, liver fibrosis, and steatosis. FXRA/sEHI treatment reduced these parameters (by 20–50%, P&lt;0.05), while OCA displayed weak or no beneficial effect on NASH (P&gt;0.05). In diet‐induced NASH model, the mice exhibited 2‐fold higher hepatic fibrosis, 2–6‐fold higher hepatic mRNA expressions of inflammatory and fibrotic markers, and marked hepatic steatosis (P&lt;0.05). The dual modulator FXRA/sEHI robustly prevented hepatic steatosis, fibrosis, and inflammation (by 50–80%, P&lt;0.05) compared to vehicle. Our results demonstrate strong potential for dual FXRA/sEHI modulators as a novel therapeutic strategy in NASH and advocate multi‐targeted approaches in NASH treatment.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Non-alcoholic steatohepatitis: The role of oxidized low-density lipoproteins

Acetyl-CoA Carboxylase Inhibition as a Therapeutic Tool in the Battle Against NASH: Hitting More Than Just One Mechanism?

Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model

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.