Fatty Liver/Adipose Tissue Dual‐Targeting Nanoparticles with Heme Oxygenase‐1 Inducer for Amelioration of Obesity, Obesity‐Induced Type 2 Diabetes, and Steatohepatitis

Abstract

Persistent uptake of high‐calorie diets induces the storage of excessive lipid in visceral adipose tissue. Lipids secreted from obese adipose tissue are accumulated in peripheral tissues such as the liver, pancreas, and muscle, and impair insulin sensitivity causing type 2 diabetes mellitus (T2DM). Furthermore, the accumulation of inflammatory cytokines and lipids in the liver induces apoptosis and fibrogenesis, and ultimately causes nonalcoholic steatohepatitis (NASH). To modulate obese tissue environments, it is challenged to selectively deliver inducers of heme oxygenase‐1 (HO‐1) to adipose tissue with the aid of a prohibitin targeting drug delivery system. Prohibitin binding peptide (PBP), an oligopeptide targeting prohibitin rich in adipose tissue, is conjugated on the surface of Hemin‐ or CoPP‐loaded poly(lactide‐co‐glycolide) nanoparticles (PBP‐NPs). PBP‐NPs efficiently differentiate lipid storing white adipocytes into energy‐generating brown adipocytes in T2DM and NASH models. In addition, PBP‐NPs are found to target prohibitin overexpressed fatty liver in the NASH model and inhibit hepatic uptake of circulating lipids. Furthermore, PBP‐NPs switch phenotypes of inflammatory macrophages in damaged organs and lower inflammation. Taken together, dual‐targeted induction of HO‐1 in fatty adipose and liver tissues is proven to be a promising therapeutic strategy to ameliorate obesity, insulin resistance, and steatohepatitis by lowering lipids and cytokines.

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

“…With this analysis, we discovered that a persistent feature within this data output was the Prohibitin signaling complex. Prohibitin-associated protein complexes have been consistently linked to many of the core functions of GPR19, i.e., stress response [165][166][167], DDR [168,169], oncogenesis [170,171], and energy metabolism [172][173][174][175]. Interestingly, we subsequently discovered that indeed PHB and MDC1 can associate with GPR19 complexes in a manner that is also sensitive to cellular perturbations that mimic aspects of the metabolic aging process.…”

Facile adipocyte uptake and liver/adipose tissue delivery of conjugated linoleic acid-loaded tocol nanocarriers for a synergistic anti-adipogenesis effect

“…Most of the injected NLCs accumulated in the liver. The lipids released from adipose tissues in obesity are deposited in peripheral organs, such as the liver [ 48 ]. It is not surprising that the nanoparticles accumulate in the liver because the liver is the main metabolic site receiving xenobiotics.…”

Diverted Mini Gastric Bypass Surgery in Obese Population: Out-turn Over Hepatic and Nephrological Parameters

“…The development of simple steatosis (SS) and nonalcoholic steatohepatitis (NASH) appear to be influenced by obesity 47 . Hepatocytes are thought to have an adipocyte-like activity when adipose tissue cannot preserve extra calories, as in disorders like lipodystrophies or typical obesity 48 . In these circumstances, the hepatic cells primarily store the additional lipids as triglycerides, which results in basic steatosis.…”