Abstract
Hypoxia and hepatosteatosis microenvironments are fundamental traits of nonalcoholic fatty liver disease (NAFLD). Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with NAFLD, whereas the route and regulation of lipid droplets (LDs) and macrophage polarization related to systemic inflammation in NAFLD is unknown. Losartan is an angiotensin II receptor antagonist, that approved portal hypertension and related HIF-1α pathways in hepatic injury models. Here, we show that losartan in a murine model of NAFLD significantly decreased hepatic de novo lipogenesis (DNL) as well as suppressed lipid droplets (LDs), LD-associated proteins, perilipins (PLINs), and cell-death-inducing DNA-fragmentation-factor (DFF45)-like effector (CIDE) family in liver and epididymal white adipose tissues (EWAT) of ob/ob mice. Obesity-mediated macrophage M1 activation was also required for HIF-1α expression in the liver and EWAT of ob/ob mice. Administration of losartan significantly diminishes obesity-enhanced macrophage M1 activation and suppresses hepatosteatosis. Moreover, HIF-1α-mediated mitochondrial dysfunction was reversed in ob/ob mice treated with losartan. Together, the regulation of HIF-1α controls LDs protein expression and macrophage polarization, which highlights a potential target for losartan in NAFLD.
Highlights
Obesity-related steatosis and nonalcoholic fatty liver disease (NAFLD) are associated with hepatic steatosis or accumulation of fat, predominantly triglycerides, that promote mitochondrial dysfunction and M1 macrophage polarization [1,2]
We evaluated the effects of losartan on NAFLD in obese models and compared their effects to improved liver function after 30 days of drug treatment. ob/ob mice displayed a significantly increased body weight, and the ratio of liver/ body weight index was compared with normal mice (Figure 1A)
Hepatic hypoxia-inducible factor-1α (HIF-1α) is activated in rodent models of diet-induced liver steatosis [28] and in human beings with NAFLD [29]
Summary
Obesity-related steatosis and nonalcoholic fatty liver disease (NAFLD) are associated with hepatic steatosis or accumulation of fat, predominantly triglycerides, that promote mitochondrial dysfunction and M1 macrophage polarization [1,2]. Obesity triggers hypoxia in adipose tissue and the small intestine, which stabilizes and activates hypoxia-inducible factor-1α (HIF-1α), a transcription factor implicated in hypoxia and hepatic lipid accumulation, resulting in adverse metabolic effects, including insulin resistance and NAFLD [1,3,4]. On the surface and/or in the vicinity of droplets, there are several structural/functional proteins such as lipid droplet proteins, lipogenic enzymes, and lipases, as well as LD-associated proteins such as perilipin families (PLIN1-PLIN5) and cell death-inducing DNA fragmentation factor-alpha (DFFA)-like effector (CIDE) proteins. PLIN1 tended to be associated with larger LDs, while expression of PLIN2 was more correlated with the presence of ballooned hepatocytes and evidence of oxidation [10]
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