Nonalcoholic Fatty Liver Disease and Insulin Resistance: New Insights and Potential New Treatments

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide. It is associated with clinical states such as obesity, insulin resistance, and type 2 diabetes, and covers a wide range of liver changes, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. Metabolic disorders, such as lipid accumulation, insulin resistance, and inflammation, have been implicated in the pathogenesis of NAFLD, but the underlying mechanisms, including those that drive disease progression, are not fully understood. Both innate and recruited immune cells mediate the development of insulin resistance and NASH. Therefore, modifying the polarization of resident and recruited macrophage/Kupffer cells is expected to lead to new therapeutic strategies in NAFLD. Oxidative stress is also pivotal for the progression of NASH, which has generated interest in carotenoids as potent micronutrient antioxidants in the treatment of NAFLD. In addition to their antioxidative function, carotenoids regulate macrophage/Kupffer cell polarization and thereby prevent NASH progression. In this review, we summarize the molecular mechanisms involved in the pathogenesis of NAFLD, including macrophage/Kupffer cell polarization, and disturbed hepatic function in NAFLD. We also discuss dietary antioxidants, such as β-cryptoxanthin and astaxanthin, that may be effective in the prevention or treatment of NAFLD.

Keywords: NAFLD/NASH; antioxidants; astaxanthin; chemokine; fibrosis; inflammation; insulin resistance; macrophage/Kupffer cells; β-cryptoxanthin.

Figure 1

Hypothesis explaining the progression of NAFLD/NASH. Overnutrition or inactivity leads to adipocyte hypertrophy and dysfunction, which are linked to chronic inflammation and insulin resistance through the recruitment and activation of immune cells such as macrophages and T-cells. Excess fat intake and obesity lead to hyperglycemia, hyperlipidemia, and the oversecretion of adipocytokines and the chemokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and monocyte chemoattractant protein (MCP)-1/C-C chemokine ligand 2 (CCL2). These factors further contribute to the development of systemic insulin resistance and hepatic steatosis. The latter causes hepatic inflammation and induces NASH and even cirrhosis. Hepatic inflammation involves the recruitment of macrophages/Kupffer cells and an M1-dominant phenotypic shift in macrophages in the liver, activating hepatic stellate cells and finally leading to liver fibrosis.

Figure 2

Association of chemokines and NASH. In adipose tissue of the obese, bone-marrow-derived monocytes are recruited from the bloodstream, predominantly via MCP-1-CCR2 signaling. The RANTES-CCR5 pathway also plays an important role in monocyte recruitment in adipose tissue. Infiltrated macrophages in obese adipose tissue undergo a phenotypic switch from alternative M2 macrophages to classical M1 macrophages. The latter secrete pro-inflammatory cytokines, which result in insulin resistance, adipokine dysfunction, and excess lipid accumulation in the liver. In the fatty liver, the recruitment and activation of immune cells, including Kupffer cells, contribute to hepatic inflammation, which is involved in hepatic stellate cell activation.

Figure 3

Novel effects of carotenoids on the progression of NASH. Carotenoids, such as β-cryptoxanthin and astaxanthin, may improve NASH by inhibiting lipid accumulation, lipid peroxidation, hepatic inflammation, and hepatic stellate cell activation. By inhibiting M1 macrophage/Kupffer cell activation and inducing a dominant shift of M2 macrophage/Kupffer cell polarization, carotenoids may inhibit hepatic steatosis, inflammation, and insulin resistance.