SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection - PubMed (original) (raw)

Review

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

Theodoros Androutsakos et al. Int J Mol Sci. 2022.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an 'umbrella' term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.

Keywords: MAFLD; NAFLD; SGLT-2; metabolic syndrome; non-alcoholic fatty liver disease; sodium-glucose co-transporter type-2 inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

SGLT-2 inhibitors as a promising therapeutic agents for treatment of NAFLD/NASH patients. SGLT-2i treatment contributes to alleviation of NAFLD by reduction of hyperglycaemia, improvement of systematic insulin resistance, elevation of caloric loss and reduction of body weight mostly due to glycosuria. Apart from that, SGLT-2i play a hepatoprotective effect through reduction of hepatic de novo lipogenesis, hepatic inflammation, apoptosis, ER-stress, oxidative stress, and increase of hepatic beta-oxidation. Reduced activation of hepatic satellite cells and p53/p21 pathways by SGLT-2i leads to amelioration of hepatic fibrosis and HCC development. FFA: Free fatty acids; DNL: De novo lipogenesis; HCC: Hepatocellular carcinoma; TC: Total cholesterol; TG: Triglycerides; LDL: Low density lipoprotein; VLDL: Very low density lipoprotein; GNG: Gluconeogenesis; HSC: Hepatic stellate cells; IR: Insulin resistance; ROS: Reactive oxygen species; ER-stress: Endoplasmic reticulum stress.

Figure 2

Structure of phlorizin and FDA-approved SGLT-2 inhibitors.

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SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection - PubMed (original) (raw)