Mitophagy in Hepatic Insulin Resistance: Therapeutic Potential and Concerns

Abstract

Metabolic syndrome, characterized by central obesity, hypertension, and hyperlipidemia, increases the morbidity and mortality of cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease, and other metabolic diseases. It is well known that insulin resistance, especially hepatic insulin resistance, is a risk factor for metabolic syndrome. Current research has shown that hepatic fatty acid accumulation can cause hepatic insulin resistance through increased gluconeogenesis, lipogenesis, chronic inflammation, oxidative stress and endoplasmic reticulum stress, and impaired insulin signal pathway. Mitochondria are the major sites of fatty acid β-oxidation, which is the major degradation mechanism of fatty acids. Mitochondrial dysfunction has been shown to be involved in the development of hepatic fatty acid–induced hepatic insulin resistance. Mitochondrial autophagy (mitophagy), a catabolic process, selectively degrades damaged mitochondria to reverse mitochondrial dysfunction and preserve mitochondrial dynamics and function. Therefore, mitophagy can promote mitochondrial fatty acid oxidation to inhibit hepatic fatty acid accumulation and improve hepatic insulin resistance. Here, we review advances in our understanding of the relationship between mitophagy and hepatic insulin resistance. Additionally, we also highlight the potential value of mitophagy in the treatment of hepatic insulin resistance and metabolic syndrome.

Mechanisms of muscle insulin resistance and the cross‐talk with liver and adipose tissue

“…Importantly, in the liver, insulin resistance originating from lipotoxicity has no link with impaired mitochondrial capacity, which has been attributed to a mitochondrial adaptation to promote increased lipolysis (Jelenik et al., 2017). More recent literature has highlighted the role of mitophagy in promoting mitochondrial fatty acid oxidation, as a consequence reducing hepatic fatty acid accumulation, leading to improved hepatic insulin resistance (Su et al., 2019). Studies showed that hepatic fatty acid accumulation resulted in an increase in the accumulation of damaged mitochondria (Wu et al., 2015); however, PINK1/Parking‐mediated mitophagy could reverse this phenomenon (Nguyen et al., 2016; Wang et al., 2019).…”

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

“…While obesity is associated with chronic inflammation that leads to insulin resistance and NAFLD [90], mitochondrial dysfunction is involved in all three metabolic disorders [102][103][104][105]. Most notably, mitochondrial defects in FAO lead to the accumulation of intracellular fatty acid metabolites such as dihydroxyglycerol and ceramides that adversely affect insulin signaling in various tissues [106][107][108]. Similarly, many of the genes that are regulated by transcription factors and NRs also play a critical role in the development of insulin resistance [109,110].…”

Silencing of miR-150-5p Ameliorates Diabetic Nephropathy by Targeting SIRT1/p53/AMPK Pathway

“…Autophagy is considered to play an important role in the pathogenesis of various diseases (Doherty and Baehrecke, 2018 ). Increasing evidence shows that autophagy can regulate many key functions of the kidney in the normal and diseased state (Su et al, 2019 ; Zhang et al, 2020 ). STZ-induced autophagy is inhibited in the proximal and early tubules of DM rats, which is associated with renal tubular hypertrophy.…”