Non-Alcoholic Fatty Liver Disease in HIV/HBV Patients - a Metabolic Imbalance Aggravated by Antiretroviral Therapy and Perpetuated by the Hepatokine/Adipokine Axis Breakdown

Abstract

Non-alcoholic fatty liver disease (NAFLD) is strongly associated with the metabolic syndrome and is one of the most prevalent comorbidities in HIV and HBV infected patients. HIV plays an early and direct role in the development of metabolic syndrome by disrupting the mechanism of adipogenesis and synthesis of adipokines. Adipokines, molecules that regulate the lipid metabolism, also contribute to the progression of NAFLD either directly or via hepatic organokines (hepatokines). Most hepatokines play a direct role in lipid homeostasis and liver inflammation but their role in the evolution of NAFLD is not well defined. The role of HBV in the pathogenesis of NAFLD is controversial. HBV has been previously associated with a decreased level of triglycerides and with a protective role against the development of steatosis and metabolic syndrome. At the same time HBV displays a high fibrogenetic and oncogenetic potential. In the HIV/HBV co-infection, the metabolic changes are initiated by mitochondrial dysfunction as well as by the fatty overload of the liver, two interconnected mechanisms. The evolution of NAFLD is further perpetuated by the inflammatory response to these viral agents and by the variable toxicity of the antiretroviral therapy. The current article discusses the pathogenic changes and the contribution of the hepatokine/adipokine axis in the development of NAFLD as well as the implications of HIV and HBV infection in the breakdown of the hepatokine/adipokine axis and NAFLD progression.

Keywords: HIV; adipokines; antiretroviral treatment; hepatitis B virus; hepatokines; metabolic syndrome; non-alcoholic fatty liver disease; oxidative stress.

Figure 1

A concise representation of the hepatokines and adipokines presented in the article and their implications in the pathogenesis of non-alcoholic fatty liver disease according to the current studies. The diagram indicates the effect of hepatokines (FGF21, selenoprotein P, fetuin A, chemerin) and of the adipokines (visfatin, resistin, adiponectin, ghrelin), against the mechanisms that drive the pathogenesis of NAFLD, namely steatosis, inflammation, fibrosis and insulin resistance and also against the development of the metabolic syndrome, namely adipogenesis, inflammation and insulin resistance. The diagram depicts the following processes: a. The effects of organokines on liver inflammation: visfatin, chemerin, leptin, resistin, fetuin A activate the NF-kB and TNF-α/IL6 pathway and induce a proinflammatory effect mediated by Kuppfer cells (KCs). The previous organokines exhibit high concentrations in NAFLD. By comparison, adiponectin, FGF21 and ghrelin exert an anti-inflammatory effect. b. The effects of organokines on liver fibrosis: visfatin, chemerin, leptin, selenoprotein P mediate the release of TGF-β in hepatic stelatte cells (HSCs), while adiponectin and FGF21 exert an antifibrotic effect. c. The additive effect of organokines against the evolution of the metabolic syndrome: visfatin, chemerin and leptin promote the metabolic syndrome through their proinflammatory and proadipogenic effect, as well as through their role in the aggravation of insulin resistance. On the other hand, adiponectin and FGF21 play a protective role against the metabolic syndrome. Organokines can stimulate each other (e.g: adiponectin and leptin with FGF21) or inhibit each other (e.g: fetuin A, leptin, selenoprotein P, resistin with adiponectin). Organokines synthesized predominantly in the liver are presented in brown and those synthesized predominantly in the adipose tissue are presented in yellow. The correlations between these different organokines are shown in blue. The serum concentrations of these organokines in NAFLD (high or low) are represented by arrows. Vi, visfatin; Re, resistin; Fe, fetuin A; Le, leptin; Ch, chemerin; Ad, adiponectin; Gh, ghrelin; SeP, selenoprotein; Re, resistin; Mf, macrophage; HC, hepatic cell; receptor.

Figure 2

A brief representation of metabolic and inflammatory mechanisms generated by HIV and HBV infections and their interference with the hepatokine/adipokine axis during the progression of non-alcoholic fatty liver disease. The figure shows: a. The effects of HIV on parenchymal liver cells: activation of CCR5 receptors of hepatocytes; the release of reactive oxygen species (ROS) and their subsequent effect on metabolic alterations inducing hepatic steatosis and non-alcoholic steatohepatitis (NASH). ROS excess also promotes lipid peroxidation and hepatocyte necrosis, which in turn aggravate liver inflammation and fibrosis either directly, through proinflammatory cytokines (TNF-α, IL6) and profibrogenic cytokines (TGF-β) or indirectly, through the ensuing proinflammatory and profibrotic response. b. The effects of HIV on non-parenchymal liver cells: both Kuppfer cells (KCs) and hepatic stellate cells (HSCs) can be regulated by HIV directly and indirectly via endotoxins (LPS), leading to the progression of the inflammatory response and fibrosis. c. The effects of HIV on adipose tissue cells: HIV ensures the transformation of these cells in cells with pro-inflammatory properties (adipocyte and preadipocyte cells, Th1/Th17-CD4ly lymphocytes and macrophages-MΦ1); HIV also promotes a disproportionate release of hepatokines and adipokines which in turn lead to liver inflammation, adipogenesis, insulin resistance and ultimately to HALS. d. The actions of HBV on hepatocytes: the induction of ROS with metabolic consequences; the changes in the concentrations belonging to hepatokines that promote fibrogenesis and hepatocellular carcinoma (HCC); the decreasing concentration of the protective hepatokine FGF21; the activation of mTOR, a metabolic receptor, stimulated by HBV protein x (HBx) e. The effect of antiretrovirals (ARVs) on the adipose tissue: ARVs favor the release of adipokines with lipogenetic role (e.g. resistin) and the reduction of anti-adipogenic adipokines (e.g. adiponectin, and leptin) f. The impact of HIV and ARVs on the occurrence of a specific metabolic syndrome, namely HIV/ARV associated lypodistrophy syndrome (HALS). HALS arises as a result of HIV-associated inflammatory changes and ARV-related impact on adipogenesis and is mediated by multiple mechanisms (adipocytes hypertrophy or atrophy, the evolution of the metabolic syndrome and the imbalance of hepatokine adipokine axis). Organokines synthesized predominantly in the liver are presented in brown and those synthesized predominantly in the adipose tissue are presented in yellow. The aggravating actions for the liver and adipose tissue are shown in pink. HC, hepatic cells; KC, Kupfer cells; HSC, hepatic stellate cells; ARV, antiretrovirals; Mϕ, macrophage; ROS, reactive oxygen species; HBx, hepatitis B virus X protein; Vis, visfatin; Re, resistin; Fe, fetuin; Le, leptin; Ch, chemerin; Ad, adiponectin; Gh, ghrelin; SeP, selenoprotein; Re, resistin; Th, T helper lymphocyte; LPS, endotoxin; receptor; apoptotic cells; TLR4, Toll-like receptor 4.