L-Theanine (LTA) is a non-protein amino acid mainly found in tea plants with many beneficial effects. Exercise exerts a wide range of benefits in metabolic health. Here, we show that exercise or gastric lavage intervention on mice with LTA improves diet-induced nonalcoholic steatohepatitis (NASH) in mice. Meanwhile, combinatory therapy shows that exercise and LTA synergistically improve obesity-related metabolic disorders and NASH phenotypes, including hepatic steatosis, inflammation, cell death and oxidative stress. In vivo studies indicate that LTA inhibits free fatty acid (FFA)-induced hepatocyte injury, including steatosis, oxidative stress and apoptosis. Knockdown of Nrf2 blunts the role of LTA in inhibiting FFA-induced hepatocyte oxidative stress and dysfunction. Mechanistically, LTA increases the α-ketoglutarate (α-KG) level in hepatocytes, which increases the transcription of Nrf2 by inducing active DNA demethylation on its promoter. Moreover, LTA promote the above α-KG/Nrf2 axis in synergy with exercise, thereby more efficiently inhibiting hepatic oxidative stress and ameliorating diet-induced NASH in mice. Our results suggest that, through promoting the α-KG/Nrf2 axis-mediated anti-oxidative pathway, the combination of LTA and exercise may provide an effective measure for the prevention and control of NASH.

Neuregulin 4 (Nrg4), an epidermal growth factor (EGF) family member, can bind to and activate the ErbB4 receptor tyrosine kinase. Nrg4 has five different isoforms by alternative splicing and performs a wide variety of functions. Nrg4 is involved in a spectrum of physiological processes including neurobiogenesis, lipid metabolism, glucose metabolism, thermogenesis, and angiogenesis. In pathological processes, Nrg4 inhibits inflammatory factor levels and suppresses apoptosis in inflammatory diseases. In addition, Nrg4 could ameliorate obesity, insulin resistance, and cardiovascular diseases. Furthermore, Nrg4 improves non-alcoholic fatty liver disease (NAFLD) by promoting autophagy, improving lipid metabolism, and inhibiting cell death of hepatocytes. Besides, Nrg4 is closely related to the development of cancer, hyperthyroidism, and some other diseases. Therefore, elucidation of the functional role and mechanisms of Nrg4 will provide a clearer view of the therapeutic potential and possible risks of Nrg4.

Krüppel-like factor 10 (KLF10), also known as TGFβ-inducible early gene-1 (TIEG1), was first found in human osteoblasts. Early studies show that KLF10 plays an important role in osteogenic differentiation. Through decades of research, KLF10 has been found to have complex functions in many different cell types, and its expression and function is regulated in multiple ways. As a downstream factor of transforming growth factor β (TGFβ)/SMAD signaling, KLF10 is involved in various biological functions, including glucose and lipid metabolism in liver and adipose tissue, the maintenance of mitochondrial structure and function of the skeletal muscle, cell proliferation and apoptosis, and plays roles in multiple disease processes, such as nonalcoholic steatohepatitis (NASH) and tumor. Besides, KLF10 shows gender-dependent difference of regulation and function in many aspects. In this review, the biological functions of KLF10 and its roles in disease states is updated and discussed, which would provide new insights into the functional roles of KLF10 and a clearer view of potential therapeutic strategies by targeting KLF10.

Higd1a is a conserved gene in evolution which is widely expressed in many tissues in mammals. Accumulating evidence has revealed multiple functions of Higd1a, as a mitochondrial inner membrane protein, in the regulation of metabolic homeostasis. It plays an important role in anti-apoptosis and promotes cellular survival in several cell types under hypoxic condition. And the survival of porcine Sertoli cells facilitated by Higd1a helps to support reproduction. In some cases, Higd1a can serve as a sign of metabolic stress. Over the past several years, a considerable amount of studies about how tumor fate is determined and how cancerous proliferation is regulated by Higd1a have been performed. In this review, we summarize the physiological functions of Higd1a in metabolic homeostasis and its pathophysiological roles in distinct diseases including cancer, nonalcoholic fatty liver disease (NAFLD), type Ⅱ diabetes and mitochondrial diseases. The prospect of Higd1a with potential to preserve mammal health is also discussed. This review might pave the way for Higd1a-based research and application in clinical practice.

Cysteine dioxygenase type 1 (CDO1), belonging to the mammalian non-heme Fe(Ⅱ) dioxygenases family, is a key enzyme for cysteine catabolism. Its activity and expression is regulated through multiple mechanisms. CDO1 is involved in a spectrum of physiological processes including lipid metabolism, adipogenesis, osteoblastic differentiation, redox homeostasis, fertility, bile acid metabolism, sulfide metabolism, and organismal growth and development. Many of these processes are regulated directly or indirectly by CDO1-mediated metabolism of cysteine. In pathophysiological processes, the degree of CDO1 promoter methylation is closely related to the progression and malignancy of tumors, and overexpression of CDO1 will promote ferroptosis of cancer cells. Moreover, CDO1 may ameliorate metabolic disorders through the taurine-mediated improvement of lipid metabolism and insulin sensitivity and improve neurodegenerative diseases by regulating cysteine level. Therefore, elucidation of the mechanisms underlying the role of CDO1 would provide a clearer view of the therapeutic potential and possible risks of targeting this important enzyme.