Non-alcoholic fatty liver disease (NAFLD) is one the fastest emerging manifestations of the metabolic syndrome worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, may culminate into cirrhosis and hepatocellular cancer (HCC) and is presently a leading cause of liver transplant. Although a steady progress is seen in understanding of the disease epidemiology, pathogenesis and identifying therapeutic targets, the slowest advancement is seen in the therapeutic field. Currently, there is no FDA approved therapy for this disease and appropriate therapeutic targets are urgently warranted. In this review we discuss the role of lifestyle intervention, pharmacological agents, surgical approaches, and gut microbiome, with regard to therapy for NASH. In particular, we focus the role of insulin sensitizers, thyroid hormone mimetics, antioxidants, cholesterol lowering drugs, incretins and cytokines as therapeutic targets for NASH. We highlight these targets aiming to optimize the future for NASH therapy.

Currently, there is limited understanding about hormonal regulation of mitochondrial turnover. Thyroid hormone (T₃) increases oxidative phosphorylation (OXPHOS), which generates reactive oxygen species (ROS) that damage mitochondria. However, the mechanism for maintenance of mitochondrial activity and quality control by this hormone is not known. Here, we used both in vitro and in vivo hepatic cell models to demonstrate that induction of mitophagy by T₃ is coupled to oxidative phosphorylation and ROS production. We show that T₃ induction of ROS activates CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, β) mediated phosphorylation of PRKAA1/AMPK (5′ AMP-activated protein kinase), which in turn phosphorylates ULK1 (unc-51 like autophagy activating kinase 1) leading to its mitochondrial recruitment and initiation of mitophagy. Furthermore, loss of ULK1 in T₃-treated cells impairs both mitophagy as well as OXPHOS without affecting T₃ induced general autophagy/lipophagy. These findings demonstrate a novel ROS-AMPK-ULK1 mechanism that couples T₃-induced mitochondrial turnover with activity, wherein mitophagy is necessary not only for removing damaged mitochondria but also for sustaining efficient OXPHOS.

Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B₁₂ (B₁₂) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH. We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B₁₂ (B₁₂) and folate (Fol) to reverse NASH features in mice and cell culture. Serum Hcy correlated with hepatic inflammation and fibrosis in NASH. Elevated hepatic Hcy induced and exacerbated NASH. Gene expression of hepatic Hcy-metabolizing enzymes was downregulated in NASH. Surprisingly, we found increased homocysteinylation (Hcy-lation) and ubiquitination of multiple hepatic proteins in NASH including the key autophagosome/lysosome fusion protein, Syntaxin 17 (Stx17). This protein was Hcy-lated and ubiquitinated, and its degradation led to a block in autophagy. Genetic manipulation of Stx17 revealed its critical role in regulating autophagy, inflammation and fibrosis during HHcy. Remarkably, dietary B₁₂/Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated β -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH. HHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B₁₂/folate also may represent a novel first-line therapy for NASH. The incidence of non-alcoholic steatohepatitis, for which there are no approved pharmacological therapies, is increasing, posing a significant healthcare challenge. Herein, based on studies in mice, primates and humans, we found that dietary supplementation with vitamin B₁₂ and folate could have therapeutic potential for the prevention or treatment of non-alcoholic steatohepatitis.

Autophagy is a cellular quality control and energy-providing process that is under strict control by intra- and extracellular stimuli. Recently, there has been an exponential increase in autophagy research and its implications for mammalian physiology. Autophagy deregulation is now being implicated in many human diseases, and its modulation has shown promising results in several preclinical studies. However, despite the initial discovery of autophagy as a hormone-regulated process by De Duve in the early 1960s, endocrine regulation of autophagy still remains poorly understood. In this review, we provide a critical summary of our present understanding of the basic mechanism of autophagy, its regulation by endocrine hormones, and its contribution to endocrine and metabolic homeostasis under physiological and pathological settings. Understanding the cross-regulation of hormones and autophagy on endocrine cell signaling and function will provide new insight into mammalian physiology as well as promote the development of new therapeutic strategies involving modulation of autophagy in endocrine and metabolic disorders.