Type 2 diabetes (T2D) is a disease characterized by heterogeneously progressive loss of islet β cell insulin secretion usually occurring after the presence of insulin resistance (IR) and it is one component of metabolic syndrome (MS), and we named it metabolic dysfunction syndrome (MDS). The pathogenesis of T2D is not fully understood, with IR and β cell dysfunction playing central roles in its pathophysiology. Dyslipidemia, hyperglycemia, along with other metabolic disorders, results in IR and/or islet β cell dysfunction via some shared pathways, such as inflammation, endoplasmic reticulum stress (ERS), oxidative stress, and ectopic lipid deposition. There is currently no cure for T2D, but it can be prevented or in remission by lifestyle intervention and/or some medication. If prevention fails, holistic and personalized management should be taken as soon as possible through timely detection and diagnosis, considering target organ protection, comorbidities, treatment goals, and other factors in reality. T2D is often accompanied by other components of MDS, such as preobesity/obesity, metabolic dysfunction associated steatotic liver disease, dyslipidemia, which usually occurs before it, and they are considered as the upstream diseases of T2D. It is more appropriate to call "diabetic complications" as "MDS-related target organ damage (TOD)", since their development involves not only hyperglycemia but also other metabolic disorders of MDS, promoting an up-to-date management philosophy. In this review, we aim to summarize the underlying mechanism, screening, diagnosis, prevention, and treatment of T2D, especially regarding the personalized selection of hypoglycemic agents and holistic management based on the concept of "MDS-related TOD".

Adipose tissues (AT) are an important endocrine organ that secretes various functional adipokines, peptides, non-coding RNAs, and acts on AT themselves or other distant tissues or organs through autocrine, paracrine, or endocrine manners. An accumulating body of evidence has suggested that many adipokines play an important role in liver metabolism. Besides the traditional adipokines such as adiponectin and leptin, many novel adipokines have recently been identified to have regulatory effects on the liver. Additionally, AT can produce extracellular vesicles (EVs) that act on peripheral tissues. However, under pathological conditions, such as obesity and diabetes, dysregulation of adipokines is associated with functional changes in AT, which may cause liver diseases. In this review, we focus on the newly discovered adipokines and EVs secreted by AT and highlight their actions on the liver under the context of obesity, nonalcoholic fatty liver diseases (NAFLD), and some other liver diseases. Clarifying the action of adipokines and adipose tissue-derived EVs on the liver would help to identify novel therapeutic targets or biomarkers for metabolic diseases.

To summarize experimental and clinical evidence on the association between tumor necrosis factor-α (TNF-α) and nonalcoholic fatty liver disease (NAFLD) and discuss potential treatment considerations.

Experimental evidence suggests that TNF-α is a cytokine with a critical role in the pathogenesis of NAFLD. Although, the production of TNF-α may be an early event during the course of nonalcoholic fatty liver (NAFL), TNF-α may play a more substantial role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and NAFLD-associated fibrosis. Moreover, TNF-α may potentiate hepatic insulin resistance, thus interconnecting inflammatory with metabolic signals and possibly contributing to the development of NAFLD-related comorbidities, including cardiovascular disease, hepatocellular carcinoma, and extra-hepatic malignancies. In clinical terms, TNF-α is probably associated with the severity of NAFLD; circulating TNF-α gradually increases from controls to patients with NAFL, and then, to patients with NASH. Given this potential association, various therapeutic interventions (obeticholic acid, peroxisome proliferator-activated receptors, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, probiotics, synbiotics, rifaximin, vitamin E, pentoxifylline, ursodeoxycholic acid, fibroblast growth factor-21, n-3 polyunsaturated fatty acids, statins, angiotensin receptor blockers) have been evaluated for their effect on TNF-α and NAFLD. Interestingly, anti-TNF biologics have shown favorable metabolic and hepatic effects, which may open a possible therapeutic window for the management of advanced NAFLD. The potential key pathogenic role of TNF-α in NAFLD warrants further investigation and may have important diagnostic and therapeutic implications.

Peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the superfamily of nuclear receptors that control the transcription of multiple genes. Although it is found in many cells and tissues, PPARγ is mostly expressed in the liver and adipose tissue. Preclinical and clinical studies show that PPARγ targets several genes implicated in various forms of chronic liver disease, including nonalcoholic fatty liver disease (NAFLD). Clinical trials are currently underway to investigate the beneficial effects of PPARγ agonists on NAFLD/nonalcoholic steatohepatitis. Understanding PPARγ regulators may therefore aid in unraveling the mechanisms governing the development and progression of NAFLD. Recent advances in high-throughput biology and genome sequencing have greatly facilitated the identification of epigenetic modifiers, including DNA methylation, histone modifiers, and non-coding RNAs as key factors that regulate PPARγ in NAFLD. In contrast, little is still known about the particular molecular mechanisms underlying the intricate relationships between these events. The paper that follows outlines our current understanding of the crosstalk between PPARγ and epigenetic regulators in NAFLD. Advances in this field are likely to aid in the development of early noninvasive diagnostics and future NAFLD treatment strategies based on PPARγ epigenetic circuit modification.

Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity. We tested the hypothesis that PXL065 would have similar efficacy but a better safety profile than Pio in patients with NASH.

Patients (≥8% liver fat, NAFLD activity score [NAS] ≥4, F1-F3) received daily doses of PXL065 (7.5, 15, 22.5 mg) or placebo 1:1:1:1 for 36 weeks. The primary endpoint was relative % change in liver fat content (LFC) on MRI-proton density fat fraction; liver histology, non-invasive tests, safety-tolerability, and pharmacokinetics were also assessed.

One hundred and seventeen patients were evaluated. All PXL065 groups met the primary endpoint (-21 to (-25% LFC, p = 0.008-0.02 vs. placebo); 40% (22.5 mg) achieved a ≥30% LFC reduction. Favorable trends in non-invasive tests including reductions in PIIINP (p = 0.02, 22.5 mg) and NAFLD fibrosis score (p = 0.04, 22.5 mg) were observed. On histology (n = 92), a ≥1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p = 0.06), and 35% (22.5 mg) vs. 17% for placebo; up to 50% of PXL065-treated patients achieved a ≥2 point NAS improvement without fibrosis worsening vs. 30% with placebo. Metabolic improvements included: HbA1c (-0.41% p = 0.003) and insulin sensitivity (HOMA-IR, p = 0.04; Adipo-IR, p = 0.002). Adiponectin increased (+114%, 22.5 mg, p <0.0001) vs. placebo. There was no dose-dependent effect on body weight or PXL065-related peripheral oedema signal. Overall, PXL065 was safe and well tolerated. Pharmacokinetics confirmed dose-proportional and higher steady state R- vs. S-Pio exposure.

Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease.

PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. A pivotal clinical trial is warranted to confirm the histological benefits reported herein.

Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease.

The efficacy and safety of insulin sensitizer in Asians with non-alcoholic steatohepatitis (NASH) remain elusive.

The double-blind, randomized, placebo-controlled trial was conducted aiming to investigate the efficacy and safety of pioglitazone in NASH patients.

A total of 90 NASH patients (66 males, age = 44.1 ± 12.7 years) were prospectively randomized into oral pioglitazone 30 mg/day (Arm A) or placebo (Arm B) for 24 weeks. The primary endpoint was the efficacy of pioglitazone in reducing inflammation and liver fat at end-of-treatment (EOT). NASH resolution/improvement without fibrosis worsening was also evaluated.

At EOT, there was a significantly decline of alanine aminotransferase (86.9 ± 34.3 to 45.7 ± 35.8 IU/L, p = 0.003) level in Arm A patients. In intention-to-treat analysis among 66 patients who completed paired biopsies, The NAFLD activity score (NAS) of 30 Arm A patients significantly decreased from 4.27 ± 1.14 at baseline to 2.53 ± 1.63 at EOT (p < 0.0001), whereas there was no significant change in patients of Arm B (3.94 ± 1.41 vs 3.94 ± 1.51, p = 1.0). NASH improvement without worsening of fibrosis was achieved in 46.7% (14/30) patients in Arm A, compared to 11.1% (4/36) patients in Arm B (p = 0.002). Liver fat content reduced (20.2 ± 9.0 to 14.3 ± 6.9%, p < 0.0001) on MRI-PDFF in Arm A compared to their counterparts. No significant difference of adverse events occurred between groups.

A 24-week pioglitazone treatment was well-tolerated and effective in improving liver histology and reducing liver steatosis in Asian NASH patients. (ClinicalTrials.gov number: NCT01068444).

The antidiabetic drug pioglitazone is, to date, the most efficacious oral drug recommended off-label for the treatment of nondiabetic or diabetic patients with biopsy-proven nonalcoholic steatohepatitis (NASH). However, weight gain and edema side effects have limited its use for NASH. Pioglitazone is a mixture of two stereoisomers ((R)-pioglitazone and (S)-pioglitazone) that interconvert in vitro and in vivo. We aimed to characterize their individual pharmacology to develop a safer and potentially more potent drug for NASH. We stabilized the stereoisomers of pioglitazone with deuterium at the chiral center. Preclinical studies with deuterium-stabilized (R)-pioglitazone (PXL065) and (S)-pioglitazone demonstrated that (R)-pioglitazone retains the efficacy of pioglitazone in NASH, including reduced hepatic triglycerides, free fatty acids, cholesterol, steatosis, inflammation, hepatocyte enlargement, and fibrosis. Although both stereoisomers inhibit the mitochondrial pyruvate carrier, PXL065 shows limited to no peroxisome proliferator-activated receptor gamma (PPARγ) activity, whereas (S)-pioglitazone appears responsible for the PPARγ activity and associated weight gain. Nonetheless, in preclinical models, both stereoisomers reduce plasma glucose and hepatic fibrosis to the same extent as pioglitazone, suggesting that these benefits may also be mediated by altered mitochondrial metabolism. In a phase 1a clinical study, we demonstrated safety and tolerability of single 7.5-mg, 22.5-mg, and 30-mg doses of PXL065 as well as preferential exposure to the (R)-stereoisomer in comparison to 45-mg pioglitazone. Conclusion: PXL065 at a dose lower than 22.5 mg is predicted to exhibit efficacy for NASH equal to, or greater than, 45-mg pioglitazone without the potentially detrimental weight gain and edema. The development of PXL065 for NASH represents a unique opportunity to leverage the therapeutic benefits of pioglitazone, while reducing or eliminating PPARγ-related side effects.

Endometrial cancer (EMC) is one of the complicated gynecological cancers, affecting more than three million women worldwide. Anticancer strategies such as chemotherapy, radiation, and surgery are found to be ineffective and are associated with patient incompliances. The aim of the present study is to repurpose non-oncological drug, i.e., Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, in the treatment of endometrial cancer. The study groups consist of 50 female Swiss albino mice, out of which 40 had endometrial cancer induced with N-ethyl-N-nitrosourea (ENU) and estradiol hexadrobenzoate (EHB). The other groups received saline, EHB, paclitaxel, and different test doses of pioglitazones. Different preliminary parameters such as weekly body weight, mean survival time, percentage increase in life span, and uterine tissue weight were analyzed along with histopathological analysis. We observed a significant change in weekly body weight, improvement in percentage life span, and partial restoration of uterine tissue weight to normal compared to a standard drug, paclitaxel. In the present preliminary evaluation, we have identified that pioglitazone exhibited a significant dose-dependent anticancer activity against ENU- and EHB-induced endometrial cancer, compared to the standard paclitaxel.

Non-alcoholic fatty liver disease (NAFLD) is among the most frequent etiologies of cirrhosis worldwide, and it is associated with features of metabolic syndrome; the key factor influencing its prognosis is the progression of liver fibrosis. This review aimed to propose a practical and stepwise approach to the evaluation and management of liver fibrosis in patients with NAFLD, analyzing the currently available literature. In the assessment of NAFLD patients, it is important to identify clinical, genetic, and environmental determinants of fibrosis development and its progression. To properly detect fibrosis, it is important to take into account the available methods and their supporting scientific evidence to guide the approach and the sequential selection of the best available biochemical scores, followed by a complementary imaging study (transient elastography, magnetic resonance elastography or acoustic radiation force impulse) and finally a liver biopsy, when needed. To help with the selection of the most appropriate method a Fagan's nomogram analysis is provided in this review, describing the diagnostic yield of each method and their post-test probability of detecting liver fibrosis. Finally, treatment should always include diet and exercise, as well as controlling the components of the metabolic syndrome, +/- vitamin E, considering the presence of sleep apnea, and when available, allocate those patients with advanced fibrosis or high risk of progression into clinical trials. The final end of this approach should be to establish an opportune diagnosis and treatment of liver fibrosis in patients with NAFLD, aiming to decrease/stop its progression and improve their prognosis.

The review describes the role of adiponectin in liver diseases in the presence and absence of surgery reported in the literature in the last ten years. The most updated therapeutic strategies based on the regulation of adiponectin including pharmacological and surgical interventions and adiponectin knockout rodents, as well as some of the scientific controversies in this field, are described. Whether adiponectin could be a potential therapeutic target for the treatment of liver diseases and patients submitted to hepatic resection or liver transplantation are discussed. Furthermore, preclinical and clinical data on the mechanism of action of adiponectin in different liver diseases (nonalcoholic fatty disease, alcoholic liver disease, nonalcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma) in the absence or presence of surgery are evaluated in order to establish potential targets that might be useful for the treatment of liver disease as well as in the practice of liver surgery associated with the hepatic resections of tumors and liver transplantation.

This study investigated the ameliorative and protective effects of long-term obestatin administration (80 nmol/kg/ intraperitoneal injection (i.p.)) on the pathogenesis of high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) in rats. Rats (n = 8/group) were divided as control, NAFLD, NAFLD + Simvastatin, NAFLD + obestatin, NAFLD then obestatin, and obestatin then NAFLD. Obestatin co -or post-therapy significantly reduced hepatomegaly and reversed hyperlipidemia, hepatic lipid accumulation, and insulin resistance (IR). Mechanistically obestatin treatments in these rats significantly prevented the increases in final body weights and food intake. Concomitantly, it enhanced circulatory adiponectin levels and hepatic signaling as evident by elevated hepatic protein levels of adiponectin receptors (adipoRII), carnitine palmitoyltransferase-1 (CPT-1), peroxisome proliferator-activated receptor- α (PPAR-α), and phosphor-AMPK (p-AMPK). In addition, obestatin enhanced total circulatory ghrelin levels and significantly increased deacylated ghrelin to acylated ghrelin (DAG/AG) ratio. These data suggest that obestatin reverses and protects against development or progression of NAFLD directly by modulating ghrelin and adiponectin signaling or indirectly by lowering food intake.

Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder closely linked with type II diabetes (T2D). The progression of NAFLD is associated with the induction of lipogenesis through hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway. An increase in lipogenesis induces endoplasmic reticulum (ER) stress and accelerates oxidative liver injury in the pathogenesis of NAFLD. Lobeglitazone, one of thiazolidinediones (TZDs), is used as an antidiabetic drug to lower serum glucose level through an increase in insulin sensitivity. It is known to improve pathological symptoms in animals and humans with NAFLD. However, the underlying molecular mechanism of the protective effects of lobeglitazone against NAFLD has not been elucidated. Here, we show that under the physiological condition of acute lipogenesis, lobeglitazone inhibits hepatic lipid synthesis, the subsequent ER stress, and ω-oxidation of fatty acids by inhibiting the mTORC1 pathway. As a result, lobeglitazone protected mice from lipogenesis-induced oxidative liver injury. Taken together, lobeglitazone might be a suitable drug for the treatment of patients with diabetes and NAFLD.

Background: Metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) is a common public health problem. Visfatin is secreted by visceral adipose tissue and is an adipocytokine. It could be a pro-inflammatory adipocytokine and is related to the metabolic syndrome and non-alcoholic fatty liver disease. This study evaluated the association between visfatin levels in patients with the metabolic syndrome with and without non-alcoholic fatty liver disease (NAFLD). Methods: In this cross-sectional study, 120 patients with metabolic syndrome were selected. They were categorized into two groups, patients with fatty liver (n=70) and without fatty liver disease (n=50). Laboratory and anthropometric options such as age, sex, systolic blood pressure, fasting blood sugar, lipid profile, liver enzymes, uric acid, visfatin, insulin, BMI, waist circumference, and TNF-α were measured. The chi-square test, Mann-Whitney, t test, Spearman and Pearson correlations were used for the data analysis. Results: There was a significant difference between the fatty liver and non-fatty liver disease with visfatin, BMI, FBS and lipid profile (p<0.05). The mean±SD level of visfatin was 37.1±1.7 ng/dl in the non-fatty liver and was 44.4±1.5 ng/dl in fatty liver participants (p=0.02). 59% of patients with metabolic syndrome had fatty liver in ultrasonography. Conclusion: According to this study, there was a correlation between visfatin levels and fatty liver disease.

Thiazolidinediones (TZDs; pioglitazone and rosiglitazone) have provided promising results in clinical trials for nonalcoholic steatohepatitis (NASH). The main purpose of this systematic review was to summarize evidence on circulating adiponectin levels in relation to histological changes following TZD treatment in patients with histologically confirmed NASH. We performed a systematic search in PubMed, Scopus and Cochrane Library. We included four studies, published between 2006 and 2012, providing data for 187 histologically confirmed NASH adult patients (105 on TZD and 82 controls) treated for 6-12months. Significant increase in adiponectin (80-178%) after TZD treatment was observed in all included studies. Improvement in steatosis following treatment was observed in all studies. A trend towards improvement in lobular inflammation was observed in all studies after pioglitazone, but not after rosiglitazone. Trends toward improvement in ballooning and fibrosis were observed in the two studies after pioglitazone using either the highest doses or the longest duration of therapy. Overall disease activity score was improved in all studies after pioglitazone, but not after rosiglitazone. Insulin resistance and liver function tests were also improved after treatment. Despite weight gain, circulating leptin was not increased after treatment. In conclusion, parallel increases in circulating adiponectin levels and histological improvement were observed in this systematic review. These results warrant further consideration of TZDs, but even more importantly point to a key role for novel potential treatments for NASH patients such as the newer selective peroxisome proliferator activated receptor-γ modulators, which increase adiponectin without significant weight gain.

Over the past decades, many drugs have been identified, that can potentially induce steatohepatitis in the predisposed individual. Classically this has been incriminated to amiodarone, perhexiline, and 4,4'-diethylaminoethoxyhexestrol (DH), all of which have been found to independently induce the histologic picture of non-alcoholic steatohepatitis (NASH). Pathogenetic mechanisms of hepatotoxicity although still evolving, demonstrate that mitochondrial dysfunction, deranged ATP production and fatty acid catabolism likely play an important role. Drugs like steroid hormones can exacerbate the pathogenetic mechanisms that lead to NASH, and other drugs like tamoxifen, cisplatin and irenotecan have been shown to precipitate latent fatty liver as well. Further research aiming to elucidate the pathogenesis of drug-induced steatosis and steatohepatitis is needed in order to better design therapeutic targets.

Leptin, the first described adipokine, interplays with hepatic metabolism. The aim of this review was to summarize available data on the association between leptin and nonalcoholic fatty liver disease (NAFLD). Leptin has a potential dual action on NAFLD experimental models, exerting a possible anti-steatotic, but also a proinflammatory and profibrogenic action. Observational clinical studies have shown higher or similar leptin levels between simple steatosis and nonalcoholic steatohepatitis (NASH) compared with controls. Interventional studies showed that circulating leptin diminishes together with body mass index after successful weight loss following lifestyle modifications or bariatric surgery. Studies providing evidence for the effect of other medications on leptin levels in NAFLD populations are limited and of low power. Data from small studies claim that recombinant leptin administration had a possibly beneficial effect on steatosis, but not fibrosis, in NAFLD patients with hypoleptinemia. Although the aforementioned dual leptin action has not yet been validated in humans, leptin administration in NAFLD patients with normoleptinemia or hyperleptinemia is discouraged. Further well-controlled studies in cautiously selected populations are needed to elucidate whether leptin has any prognostic and therapeutic role in NAFLD patients.

Sirtuin (Sirt), a sensor of the cell metabolic state, regulates glucose and lipid metabolism. The aim of this study was to address whether rosiglitazone (RGZ) alters hepatic Sirt1 and whether Sirt1 and/or Sirt6 have a regulatory role in the protective effects of RGZ on hepatocyte steatosis.

To investigate the effect of RGZ on hepatic Sirt1, rats were administered with RGZ for 6 weeks. The involvement of Sirt1/6 in the RGZ-mediated effect against hepatic steatosis was evaluated by single or double knockdown of Sirt1 and Sirt6 in a hepatocyte steatosis model.

RGZ in vivo increased Sirt1 expression and its activity in rat livers. In a hepatocyte steatosis model, RGZ significantly reduced lipid accumulation and activated the Sirt1/6-LKB1-AMPK pathway. Sirt1 knockdown abolished the effects of RGZ with regard to hepatocyte fat accumulation and the Sirt1/6-LKB1-AMPK pathway, suggesting that Sirt1 is a key regulator of RGZ-mediated metabolic processes. Sirt6 knockdown inhibited the protective effects of RGZ to a lesser extent than Sirt1, and double knockdown of Sirt1/6 showed no synergistic effects.

Our results demonstrate that Sirt1/6 are involved in the RGZ-mediated effects on hepatocyte steatosis, and the regulatory effects of Sirt1 and Sirt6 are not synergistic but compensatory for improving hepatocyte steatosis.

An update on pharmacotherapy for achieving and maintaining abstinence and mitigating hepatic damage in patients with alcoholic liver disease (ALD) is presented.

Currently there are limited pharmacotherapy options for managing ALD, which encompasses a broad spectrum of disorders ranging from steatosis and alcoholic hepatitis to fibrosis, cirrhosis, and hepatocellular cancer. Individual variation in the severity, presentation, and complex pathologenesis of ALD defines barriers to effective treatment. Scoring of disease severity using validated assessment instruments should guide treatment approaches; abstinence and proper nutrition continue to be the cornerstones of management. A literature search (through December 31, 2013) identified no reports of randomized controlled trials using Food and Drug Administration (FDA)-approved medications for the treatment of alcohol dependence in ALD-spectrum disorders. Disulfiram, acamprosate, and naltrexone (oral and intramuscular), while approved by FDA for treatment of alcohol dependence, are not currently approved for use in patients with ALD. Baclofen (also not FDA-approved for use in ALD) is the only medication available in the United States with demonstrated safety and efficacy in reducing alcoholic behavior that has been formally tested in clinical trials in patients with ALD. Pharmacotherapy of alcoholic hepatitis using glucocorticoids or pentoxifylline has shown promise, but these options are reserved for severe ALD only.

Although various treatments have been investigated for ALD in patients with alcoholism, complete abstinence from alcohol is currently the only recommended form of hepatoprotection for the entire spectrum of ALD diagnoses.

Diabetes is associated with a spectrum of liver diseases including nonalcoholic liver disease, steatohepatitis, and liver cirrhosis with their increased complications and mortality. Hepatitis C virus (HCV) and its associated liver cirrhosis has been associated with diabetes through insulin resistance. Cryptogenic diabetes occurs as a consequence of liver cirrhosis with the pathophysiology being complex, but mostly attributed to the increased insulin resistance in muscle, liver, and adipose tissue. As for the management of diabetes in patients with liver disease, lifestyle modification plays an important role. Oral diabetic medications are contraindicated in patients with advanced liver diseases with associated cirrhosis, ascites, or encephalopathy. As for stable liver disease, metformin and thiazolenediones have shown mixed results, with some showing them to be effective in improving liver transaminases in addition to histological improvement in steatosis and inflammation. α-glucosidase inhibitors may be helpful in decreasing hepatic encephalopathy. Upregulation of Dipeptidyl peptidase-4 (DPP-4) has been suggested as a possible pathogenetic mechanism for HCV-related insulin resistance, and treatment with DPP-4 inhibitors could improve insulin sensitivity in diabetic patients with liver disease. Patients with impaired liver function with associated insulin resistance may need increased insulin requirements. On the other hand patients with altered liver metabolism might need decreased insulin requirements.

Novel peroxisome proliferator-activated receptor (PPAR) modulators (selective PPAR modulators [SPPARMs]) and dual PPAR agonists may have an important role in the treatment of cardiometabolic disorders owing to lipid-modifying, insulin-sensitizing and anti-inflammatory effects.

This review summarizes the efficacy of new PPAR agonists and SPPARMs that are under development for the treatment of atherogenic dyslipidemia and non-alcoholic fatty liver disease (NAFLD).

ABT-335 is a new formulation of fenofibrate that has been approved for concomitant use with statins. K-877, a SPPARM-α with encouraging preliminary results in modulating atherogenic dyslipidemia, and INT131, a SPPARM-γ with predominantly insulin-sensitizing actions, may also have favorable lipid-modifying effects. Although the development of dual PPAR-α/γ agonists (glitazars) and the SPPARM-δ GW501516 has been abandoned because of safety issues, another SPPARM-δ (MBX-8025) and a dual PPAR-α/δ agonist (GFT-505) have shown promising efficacy in decreasing plasma triglyceride and increasing high-density lipoprotein cholesterol concentrations, as well as improving insulin sensitivity and liver function. The beneficial effects of GFT-505 are complemented by preclinical findings that indicate reduction of hepatic fat accumulation, inflammation and fibrosis, making it a promising candidate for the treatment of NAFLD/nonalcoholic steatohepatitis (NASH). Long-term trials are required to test the efficacy and safety of these new PPAR agonists in reducing cardiovascular outcomes and treating NAFLD/NASH.

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver damage ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. To date, no pharmacological treatment is approved for NAFLD/NASH. Here, we report on preclinical and clinical data with GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ) agonist. In the rat, GFT505 concentrated in the liver with limited extrahepatic exposure and underwent extensive enterohepatic cycling. The efficacy of GFT505 was assessed in animal models of NAFLD/NASH and liver fibrosis (Western diet [WD]-fed human apolipoprotein E2 [hApoE2] transgenic mice, methionine- and choline-deficient diet-fed db/db mice, and CCl4 -induced fibrosis in rats). GFT505 demonstrated liver-protective effects on steatosis, inflammation, and fibrosis. In addition, GFT505 improved liver dysfunction markers, decreased hepatic lipid accumulation, and inhibited proinflammatory (interleukin-1 beta, tumor necrosis factor alpha, and F4/80) and profibrotic (transforming growth factor beta, tissue inhibitor of metalloproteinase 2, collagen type I, alpha 1, and collagen type I, alpha 2) gene expression. To determine the role of PPAR-α-independent mechanisms, the effect of GFT505 was assessed in hApoE2 knock-in/PPAR-α knockout mice. In these mice, GFT505 also prevented WD-induced liver steatosis and inflammation, indicating a contribution of PPAR-α-independent mechanisms. Finally, the effect of GFT505 on liver dysfunction markers was assessed in a combined analysis of four phase II clinical studies in metabolic syndrome patients. GFT505 treatment decreased plasma concentrations of alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase.

The dual PPAR-α/δ agonist, GFT505, is a promising liver-targeted drug for treatment of NAFLD/NASH. In animals, its protective effects are mediated by both PPAR-α-dependent and -independent mechanisms.

The prevalence of metabolic syndrome, obesity and insulin resistance has become an epidemic in the world. A strong association exists between metabolic syndrome and non-alcoholic fatty liver disease (NAFLD), though the etiology of NAFLD is still unclear. This close association leads to numerous clinical studies to investigate the effects of insulin sensitizers, thiazolidinediones (TZDs), on hepatic fat accumulation. Thiazolidinediones affect glucose and lipid metabolism in insulin-sensitive tissues, which in turn reduces the lipid content in the liver by modulating several mediators. In the present review, we discuss key modulators - adiponectin and sirtulin-adenosine monophosphate activated protein kinase signaling - as the mechanisms responsible for NAFLD related to metabolic syndrome.

Leptin is an adipocyte-secreted hormone that has been proposed to regulate energy homeostasis as well as metabolic, reproductive, neuroendocrine, and immune functions. In the context of open-label uncontrolled studies, leptin administration has demonstrated insulin-sensitizing effects in patients with congenital lipodystrophy associated with relative leptin deficiency. Leptin administration has also been shown to decrease central fat mass and improve insulin sensitivity and fasting insulin and glucose levels in HIV-infected patients with highly active antiretroviral therapy (HAART)-induced lipodystrophy, insulin resistance, and leptin deficiency. On the contrary, the effects of leptin treatment in leptin-replete or hyperleptinemic obese individuals with glucose intolerance and diabetes mellitus have been minimal or null, presumably due to leptin tolerance or resistance that impairs leptin action. Similarly, experimental evidence suggests a null or a possibly adverse role of leptin treatment in nonlipodystrophic patients with nonalcoholic fatty liver disease. In this review, we present a description of leptin biology and signaling; we summarize leptin's contribution to glucose metabolism in animals and humans in vitro, ex vivo, and in vivo; and we provide insights into the emerging clinical applications and therapeutic uses of leptin in humans with lipodystrophy and/or diabetes.

Additional drugs are required to effectively manage diabetes and its complications. Recent studies have revealed protective effects of Ad36, a human adenovirus, and its E4orf1 protein on glucose disposal, which may be creatively harnessed to develop novel anti-diabetic agents. Experimental Ad36 infection improves hyperglycemia in animal models and natural Ad36 infection in humans is associated with better glycemic control. Available data indicate distinctive advantages for a drug that may mimic the action of Ad36/E4orf1. The key features of such a potential drug include the ability to increase glucose uptake by adipose tissue and skeletal muscle, to reduce hepatic glucose output independent of proximal insulin signaling, and to up-regulate adiponectin and its hepatic action. The effect of Ad36/E4orf1 on hepatocyte metabolism suggests a role for treating hepatic steatosis. Despite these potential advantages, considerable research is required before such a drug is developed. The in vivo efficacy and safety of E4orf1 in improving hyperglycemia remain unknown, and an appropriate drug delivery system is required. Nonetheless, Ad36 E4orf1 offers a research opportunity to develop a new anti-diabetic agent with multiple potential advantages and conceptually advances the use of a rather unconventional source, microbial proteins, for anti-diabetic drug development.

Hepatic fibrosis is a dynamic chronic liver disease occurring as a consequence of wound-healing responses to various hepatic injuries. This disorder is one of primary predictors for liver-associated morbidity and mortality worldwide. To date, no pharmacological agent has been approved for hepatic fibrosis or could be recommended for routine use in clinical context. Cellular and molecular understanding of hepatic fibrosis has revealed that peroxisome proliferator-activated receptor-γ (PPARγ), the functioning receptor for antidiabetic thiazolidinediones, plays a pivotal role in the pathobiology of hepatic stellate cells (HSCs), whose activation is the central event in the pathogenesis of hepatic fibrosis. Activation of PPARγ inhibits HSC collagen production and modulates HSC adipogenic phenotype at transcriptional and epigenetic levels. These molecular insights indicate PPARγ as a promising drug target for antifibrotic chemotherapy. Intensive animal studies have demonstrated that stimulation of PPARγ regulatory system through gene therapy approaches and PPARγ ligands has therapeutic promise for hepatic fibrosis induced by a variety of etiologies. At the same time, thiazolidinedione agents have been investigated for their clinical benefits primarily in patients with nonalcoholic steatohepatitis, a common metabolic liver disorder with high potential to progress to fibrosis and liver-related death. Although some studies have shown initial promise, none has established long-term efficacy in well-controlled randomized clinical trials. This comprehensive review covers the 10-year discoveries of the molecular basis for PPARγ regulation of HSC pathophysiology and then focuses on the animal investigations and clinical trials of various therapeutic modalities targeting PPARγ for hepatic fibrosis.

Osteoporosis and obesity are chronic disorders that are both increasing in prevalence. The pathophysiology of these conditions is multifactorial and includes genetic, environmental and hormonal determinants. Although it has long been considered that these are distinct disorders rarely found in the same individual, emerging evidence from basic and clinical studies support an important interaction between adipose tissue and the skeleton. It is proposed that adiposity may influence bone remodelling through three mechanisms: (i) secretion of cytokines that directly target bone, (ii) production of adipokines that influence the central nervous system thereby changing sympathetic impulses to bone and (iii) paracrine influences on adjacent skeletal cells. Here we focus on the current understanding of bone-fat interactions and the clinical implications of recent studies linking obesity to osteoporosis.

Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that exert in the liver a transcriptional activity regulating a whole spectrum of physiological functions, including cholesterol and bile acid homeostasis, lipid/glucose metabolism, inflammatory responses, regenerative mechanisms, and cell differentiation/proliferation. Dysregulations of the expression, or activity, of specific PPAR isoforms in the liver are therefore believed to represent critical mechanisms contributing to the development of hepatic metabolic diseases, disorders induced by hepatic viral infections, and hepatocellular adenoma and carcinoma. In this regard, specific PPAR agonists have proven to be useful to treat these metabolic diseases, but for cancer therapies, the use of PPAR agonists is still debated. Interestingly, in addition to previously described mechanisms regulating PPARs expression and activity, microRNAs are emerging as new important regulators of PPAR expression and activity in pathophysiological conditions and therefore may represent future therapeutic targets to treat hepatic metabolic disorders and cancers. Here, we reviewed the current knowledge about the general roles of the different PPAR isoforms in common chronic metabolic and infectious liver diseases, as well as in the development of hepatic cancers. Recent works highlighting the regulation of PPARs by microRNAs in both physiological and pathological situations with a focus on the liver are also discussed.

Peroxisome proliferator-activated receptors-γ (PPARγs) are ligand-activated transcription factors that play a crucial regulatory role in the transcription of a large number of genes involved in lipid metabolism and inflammation. In addition to physiological ligands, synthetic ligands (the thiazoledinediones) have been developed. In spite of the much publicized adverse cardiovascular effects of one such thiazoledinedione (rosiglitazone), PPARγ activation may have beneficial cardiovascular effects. In this article we review the effects of PPARγ activation on the endothelium with special emphasis on the possible implications in cardiovascular disease. We discuss its possible role in inflammation, vasomotor function, thrombosis, angiogenesis, vascular aging and vascular rhythm. We also briefly review the clinical implications of these lines of research.

B cell-activating factor (BAFF) is expressed in adipocytes and affects lipogenesis and insulin sensitivity. In addition, the BAFF receptor is expressed in visceral adipose tissue and liver. The aim of this study was to analyze serum BAFF levels in patients with nonalcoholic steatohepatitis (NASH) and simple steatosis (SS) and to compare their respective clinical and histological findings.

A total of 96 patients with nonalcoholic fatty liver disease (20 with SS and 76 with NASH) were enrolled and their serum BAFF levels were analyzed. Comprehensive blood chemistry analysis and histological examination of liver samples were also conducted.

Serum BAFF levels were higher in patients with NASH than in those with SS (p = 0.016). NASH patients with ballooning hepatocytes and advanced fibrosis had higher levels of BAFF in sera (p = 0.016 and p = 0.006, respectively). In addition, the prevalence of NASH increased significantly as the serum BAFF level increased (p = 0.004). Higher serum BAFF levels were found to be an independent risk factor for development of NASH (OR 1.003, 95% CI 1.0003-1.006; p = 0.047).

Nonalcoholic steatohepatitis patients had higher levels of serum BAFF than patients with SS, and higher levels were associated with the presence of hepatocyte ballooning and advanced fibrosis. The serum BAFF level may be a useful tool for distinguishing NASH from SS.

Non-alcoholic fatty liver disease (NAFLD) is a liver pathology with increasing prevalence due to the obesity epidemic. Hence, NAFLD represents a rising threat to public health. Currently, no effective treatments are available to treat NAFLD and its complications such as cirrhosis and liver cancer. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate lipid and glucose metabolism as well as inflammation. Here we review recent findings on the pathophysiological role of PPARs in the different stages of NAFLD, from steatosis development to steatohepatitis and fibrosis, as well as the preclinical and clinical evidence for potential therapeutical use of PPAR agonists in the treatment of NAFLD. PPARs play a role in modulating hepatic triglyceride accumulation, a hallmark of the development of NAFLD. Moreover, PPARs may also influence the evolution of reversible steatosis toward irreversible, more advanced lesions. Presently, large controlled trials of long duration are needed to assess the long-term clinical benefits of PPAR agonists in humans. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

The rationale for specific pharmacologic therapy in nonalcoholic steatohepatitis (NASH) is determined by the potential for disease progression and the difficulties, in many patients, of successfully implementing diet and lifestyle changes over the long term. Owing to their ability to correct insulin resistance, insulin-sensitizing agents are attractive candidates for the treatment of NASH. In this review we provide an insight into the mechanism of action, therapeutic efficacy and safety issues regarding the use of glitazones in NASH.

Insulin resistance has an important role in the development of nonalcoholic fatty liver disease (NAFLD) and is involved in both pathological processes: hepatic steatosis and atherosclerosis. Therefore, treatment of NAFLD with insulin sensitizers is likely to have a favorable effect toward hepatic steatosis and cardiovascular outcomes. The present study investigated the effect of metformin on arterial properties, metabolic parameters, and liver function in patients with NAFLD. In a randomized, placebo-controlled study, 63 patients with NAFLD were assigned to 1 of 2 groups: Group 1 received daily metformin; group 2 received placebo. Pulse wave velocity (PWV) and augmentation index (AI) were measured using SphygmoCor (version 7.1; AtCor Medical, Sydney, Australia) at baseline and at the end of the 4-month treatment period. Metabolic measures and serum adiponectin levels were determined. Among metformin-treated patients, PWV and AI decreased significantly during the study. Significant declines in fasting glucose, triglyceride, and alkaline phosphatase and a significant increase in high-density lipoprotein cholesterol were observed. Alanine aminotransferase decreased and serum adiponectin increased marginally. In the placebo group, neither PWV nor AI improved significantly during the treatment period. Alanine aminotransferase, aspartate aminotransferase, and adiponectin did not change in the placebo group. Metformin treatment was associated with significant decrease in PWV and AI in NAFLD patients. This beneficial vascular effect was accompanied by an improvement in glucose and lipid metabolism as well as liver enzymes.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease in the world. It encompasses a histological spectrum, ranging from simple, nonprogressive steatosis to nonalcoholic steatohepatitis (NASH), which may progress to cirrhosis and hepatocellular carcinoma. While liver-related complications are confined to NASH, emerging evidence suggests both simple steatosis and NASH predispose to type 2 diabetes and cardiovascular disease. The pathogenesis of NAFLD is currently unknown, but accumulating data suggest that oxidative stress and altered redox balance play a crucial role in the pathogenesis of steatosis, steatohepatitis, and fibrosis. We will examine intracellular mechanisms, including mitochondrial dysfunction and impaired oxidative free fatty acid metabolism, leading to reactive oxygen species generation; additionally, the potential pathogenetic role of extracellular sources of reactive oxygen species in NAFLD, including increased myeloperoxidase activity and oxidized low density lipoprotein accumulation, will be reviewed. We will discuss how these mechanisms converge to determine the whole pathophysiological spectrum of NAFLD, including hepatocyte triglyceride accumulation, hepatocyte apoptosis, hepatic inflammation, hepatic stellate cell activation, and fibrogenesis. Finally, available animal and human data on treatment opportunities with older and newer antioxidant will be presented.

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome, which includes dyslipidemia, central obesity, hypertension, and insulin resistance. These diseases collectively and individually increase the risk of cardiovascular disease. Nonalcoholic steatohepatitis (NASH) is a subset of NAFLD that can progress to cirrhosis in up to 30% of patients and lead to decompensated liver disease requiring liver transplantation in many patients. Insulin resistance is the pathophysiological hallmark of NASH and addressing insulin resistance is an important aspect of NASH management. Lifestyle modifications with diet and exercise improve insulin sensitivity and are the cornerstone of therapy, but are often difficult to maintain long term. Not surprisingly, insulin-sensitizing agents have been a focus of pharmacologic investigation in NASH. Insulin sensitizers such as the thiazolidinediones, biguanides, glucagon-like peptide-1 receptor agonists, and the dipeptidyl peptidase IV inhibitors, also known as incretins, will be discussed with respect to their mechanism of action and how these drugs might target aspects of NASH pathophysiology. Finally, we will summarize the available clinical data and review both the risks and benefits of insulin sensitizers in the treatment of NASH.

Although diet and lifestyle changes are the first-line therapy in patients with non-alcoholic steatohepatitis (NASH), few patients are able to successfully implement these measures over the long run while others have an advanced disease requiring specific pharmacological therapy. Because insulin resistance is the underlying condition favoring the occurrence of NASH, insulin sensitizers have been tested in this condition although available trials are heterogenous in terms of choice of the drug, dosage, length of therapy and patient profile. Overall, thiazolidinediones reduce aminotransferase levels and induce a strong anti-steatogenic response. Most studies have shown an improvement in inflammation and liver cell injury while none have convincingly demonstrated an effect on fibrosis regression. The optimal duration of therapy is unknown as prolonged therapy does not seem to induce additional histological benefit. Although some tolerance issues and safety concerns, in particular cardiovascular, have been raised, thiazolidinediones are the class of drugs with the largest body of evidence in the treatment of NASH so far and can be successfully used in some patients with this disease.

Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.

The mechanisms whereby hepatic fibrosis develops in chronic liver diseases remain incompletely defined. Here, we sought to examine whether microRNA (miRNA) became dysregulated in dimethylnitrosamine-induced hepatic fibrosis in rats. Our microarray analysis revealed that the miR-34 family was upregulated along with other miRNAs in liver fibrotic tissues. Six miRNAs, such as rno-miR-878, were downregulated. The findings were confirmed by RT-PCR assays. Gene ontology analysis further showed that many of these dysregulated miRNAs were involved in lipid/fatty acid metabolism. The acyl-CoA synthetase long-chain family member 1 (ACSL1) gene contained specific binding sites for miR-34a/miR-34c. Additional enhanced green fluorescence protein reporter activity assays indicated that the miR-34 family targeted ACSL1. Our RT-PCR and immunoblotting assays further demonstrated that both the mRNA and protein levels of ACSL1 were markedly reduced in fibrotic liver tissues. Our findings suggest that miRNA becomes dysregulated during hepatic fibrosis, and that the miR-34 family may be involved in the process by targeting ACSL1.

Insulin sensitizers are attractive candidate therapies for nonalcoholic steatohepatitis mainly because of the strong association between this disease and insulin resistance. This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis. It also highlights methodological challenges for trial design and proposes endpoints for future proof of principle, registrational, and postmarketing trials.

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the Western world, is tightly associated with obesity and metabolic syndrome. NAFLD entails an increased cardiometabolic and liver-related risk, the latter regarding almost exclusively non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Pathogenetic models encompass altered hepatic lipid partitioning and adipokine action, increased oxidative stress, free fatty acid lipotoxicity. On this basis, lifestyle-, drug- or surgically induced weight loss, insulin sensitizers, antioxidants, lipid-lowering drugs have been evaluated in NAFLD/NASH. Most trials are small, of short duration, nonrandomized, without histological end points, thus limiting assessment of long-term safety and efficacy of proposed treatments. All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver-related risk. Liver biopsy remains the gold standard for staging NAFLD, but non-invasive methods are under intense development. Weight loss through lifestyle intervention is the initial approach, because of established efficacy on NAFLD-associated cardiometabolic abnormalities, and to emerging benefits on necroinflammation and overall disease activity in NASH. Bariatric surgery warrants further evaluation before it can be routinely considered in morbidly obese NASH. Larger- and longer-duration randomized trials assessing safety and benefits of drugs on patient-oriented outcomes are needed before pharmacological treatment can be routinely recommended for NASH.

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of chronic liver disease in Western countries and the leading cause of cryptogenic cirrhosis. Insulin resistance (IR) is a key factor in the pathogenesis of NAFLD, the latter being considered as the hepatic component of IR or metabolic syndrome (MetS). Although the pathogenesis of NAFLD is not fully elucidated, a complex interaction between adipokines and cytokines produced by adipocytes and/or inflammatory cells infiltrating adipose tissue appears to play a crucial role in MetS and NAFLD. Adiponectin is the most abundant and adipose-specific adipokine. In the liver, adiponectin acts through the activation of 5-AMP-activated protein kinase and peroxisome proliferator-activated receptor-alpha pathways and inhibition of toll-like receptor-4 mediated signalling. There is an evidence that adiponectin decreases hepatic and systematic IR and attenuates liver inflammation and fibrosis. Adiponectin generally predicts steatosis grade and severity of NAFLD, but it remains to be addressed to what extent this is a direct effect or related to the presence of more severe IR. Although there is no proven pharmacotherapy for the treatment of NAFLD, recent therapeutic strategies have focused on the indirect upregulation of adiponectin through the administration of various therapeutic agents and/or lifestyle modifications. Weight loss, through diet, lifestyle changes and/or medications including orlistat, sibutramine, rimonabant or bariatric surgery, increase adiponectin and may improve liver histology. Insulin sensitizers, including pioglitazone and rosiglitazone, and lipid-lowering agents, including statins and fibrates, also upregulate adiponectin and ameliorate liver histology. The wider use of new treatment approaches appears to signal the dawn of a new era in the management of NAFLD. In this adiponectin-focused review, the pathogenetic role and the potential therapeutic benefits of adiponectin in NAFLD are systematically analysed.

Nonalcoholic fatty liver disease (NAFLD), first described in 1980, is now recognized as one of the most common causes of elevated liver enzymes and chronic liver disease in Western countries. The incidence of NAFLD in both adults and children is rising, in conjunction with the burgeoning epidemics of obesity and type 2 diabetes mellitus. NAFLD often coexists with other sequelae of the metabolic syndrome: central obesity, type 2 diabetes, hypertension, and hyperlipidemia. NAFLD encompasses a spectrum of pathologic liver diseases ranging from simple hepatic steatosis to a predominant lobular necro-inflammation, with or without centrilobular fibrosis (called nonalcoholic steatohepatitis or NASH). NASH can progress to cirrhosis, decompensated liver disease, and hepatocellular carcinoma. Though the natural history of NASH is still not clearly defined, it has been observed to progress to cirrhosis in 15%-220% of those affected. Insulin resistance is nearly universal in NASH and is thought to play an important role in its pathogenesis leading to dysregulated lipid metabolism. The prevalence of insulin resistance is reported in the general population to be approaching 45%, suggesting that NAFLD and NASH will contin nue to be an important public health concern. To date, NASH has proven to be a difficult disease to treat. Front-line therapy with lifestyle modifications resulting in weight loss through decreased caloric intake and moderate exercise is generally believed to be beneficial in patients with NASH, but is often difficult to maintain long term. Given that insulin resistance plays a dominant role in the pathogenesis, many studies have examined the use of insulin sensitizers: the biguanides (metformin), thiazolidinediones (pioglitazone, troglitazone, and rosiglitazone), glucagon-like peptide-1-receptor agonists, or incretins (exenatide)in NASH. This review will provide an overview of insulin resistance in NAFLD and provide a detailed summary on the clinical data regarding the use of insulin sensitizers in NASH.

Alcohol abuse causes progressive toxicity and degeneration in liver and brain due to insulin resistance, which exacerbates oxidative stress and pro-inflammatory cytokine activation. Alcohol-induced steatohepatitis promotes synthesis and accumulation of ceramides and other toxic lipids that cause insulin resistance. Ceramides can readily cross the blood-brain barrier, and ceramide exposure causes neurodegeneration with insulin resistance and oxidative stress, similar to the effects of alcohol. Therefore, in addition to its direct neurotoxic effects, alcohol misuse establishes a liver-brain axis of neurodegeneration mediated by toxic lipid trafficking across the blood-brain barrier, leading to progressive white matter degeneration and cognitive impairment.

Hepatic steatosis (fatty liver) is increasingly recognized as a major component of the metabolic (insulin resistance) syndrome. It can progress to cirrhosis and hepatocellular carcinoma, leading to liver-related mortality. Increasing evidence shows a significant association between hepatic steatosis and hypertension; both are linked to the metabolic syndrome. This review discusses the evidence to support this association, and reviews the diagnosis and management of hepatic steatosis.

The obesity epidemic has now spread worldwide. With increase in weight, there is an increase in dysregulated energy metabolism ultimately leading to dysfunction of multiple organ systems recognized as the metabolic syndrome. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide, and is thought to be the hepatic manifestation of metabolic syndrome. It is a nondiscriminating disease affecting both children and adults and no socioeconomic class is spared. There is a well-defined increase in both liver-related and all-cause mortality. Current projections foresee a continued worsening in prevalence, especially with the increased rate of childhood obesity. Prevention would be the ultimate goal, but with continued trends in obesity, therapeutic options are needed to manage this chronic liver disease and prevent its complications of cirrhosis and even hepatocellular carcinoma. Therapies will need to be affordable, tolerable, and safe to be useful on such a large scale. This article will discuss some of the basic understanding of NAFLD, as well as review the currently tested therapies, some novel therapies, and potential future therapeutic options.