science

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that act as transcription factors for gene expression by binding to specific DNA sequences. They have been shown to have a role in several physiological processes including carbohydrate and lipid metabolism as well as inflammation and fibrogenesis, and represent a promising target for therapy.

The PPAR family comprises three isoforms: PPARα, PPARβ/δ and PPARγ, which are differentially expressed in various tissues.

PPARα is expressed ubiquitously but most highly in the liver. PPAR-α plays a critical role in the regulation of fatty acid transport and β-oxidation and triglyceride turnover, is involved in regulation of energy homeostasis and is thought to have anti-inflammatory effects through complex regulation of nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) and activator protein 1 (AP1) transcription factors.

PPARβ/δ is expressed mainly in skeletal muscle and to a lesser degree in adipose tissue and liver. PPARβ/δ contributes to the regulation of glucose and lipid metabolism and is involved in regulating mitochondrial metabolism and fatty acid β-oxidation in muscle. It is also present in Kupffer cells and HSCs, and may, therefore, have a role in inflammation and fibrosis since HSCs as well as portal fibroblasts are the main source of hepatic myofibroblasts. Furthermore, PPARβ/δ is also expressed in vascular cells including endothelial cells, smooth muscle cells and macrophages, and it plays an important role in various basic vascular processes such as apoptosis, survival, angiogenesis and inflammation.

PPARγ is highly expressed in adipose tissue and plays an essential role in the regulation of adipocyte differentiation, adipogenesis and lipid metabolism; its activation induces insulin sensitization, enhances glucose metabolism, increases triglyceride storage in adipocytes while decreasing liver steatosis in humans. In addition, it stimulates secretion of the anti-inflammatory cytokine adiponectin. PPARγ is also expressed in HSCs where it plays a key role in maintaining them inactive. Furthermore, forced expression of PPARγ has been shown to reverse activated HSCs to their quiescent state.

Both PPARα-β/δ dual agonism as well as PPARγ agonism have shown beneficial effects on liver histology in phase IIb clinical trials for NASH. Single, dual and pan-PPAR agonists are under development for the pharmacological treatment of NASH.

Lifestyle interventions

The close relationship between unhealthy lifestyle and NAFLD makes lifestyle correction mandatory in all patients, with the potential not only to improve liver disease, but also hyperglycaemia, atherogenic dyslipidaemia and high blood pressure. Relatively small amounts of weight loss reduce liver fat and improve hepatic insulin resistance.

Lifestyle interventions

Bariatric surgery is an efficient method to achieve significant weight loss, reverse insulin resistance, and reduce cardiovascular risk and long-term mortality. A meta-analysis on the effect of bariatric surgery in NAFLD revealed that the pooled proportion of patients with improvement or resolution was 91.6% for steatosis, 81.3% for steatohepatitis, 65.5% for fibrosis, and that 69.5% of patients experienced complete resolution of NASH. Nevertheless, the AASLD practice guidance states that while bariatric surgery can be considered in otherwise eligible patients with NAFLD or NASH, it is premature to consider it as an established option for the treatment of NASH.

PHARMACOTHERAPY: LACK OF APPROVED THERAPIES

European and U.S. guidelines recommend that pharmacotherapy should be reserved for patients with biopsy-proven NASH, particularly those with significant fibrosis (stage F2 and higher), but also those with early-stage NASH who are at high risk of disease progression. As yet, no drugs have been approved for treatment of NASH and thus any recommendation for pharmacological therapy is off label. However, the EASL-EASD-EASO guideline states that pioglitazone or vitamin E or their combination may be used for NASH.

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