Aging is associated with dysregulation of glucose and lipid metabolism. Various factors that contribute to the dysregulation include both modifiable (e.g. obesity, insulin resistance) and ...non-modifiable risk factors (age-associated physiologic changes). Although there is no linear relationship between aging and prevalence of non-alcoholic fatty liver disease, current data strongly suggests that advanced age leads to more severe histological changes and poorer clinical outcomes. Hepatic lipid accumulation could lead to significant hepatic and systemic consequences including steatohepatitis, cirrhosis, impairment of systemic glucose metabolism and metabolic syndrome, thereby contributing to age-related diseases. Insulin, leptin and adiponectin are key regulators of the various physiologic processes that regulate hepatic lipid metabolism. Recent advances have expanded our understanding in this field, highlighting the role of novel mediators such as FGF 21, and mitochondria derived peptides. In this review, we will summarize the mediators of hepatic lipid metabolism and how they are altered in aging.
•Aging increases the risk for non-alcoholic fatty liver disease (NAFLD) and associated comorbidities.•Impaired fatty acid oxidation and increased de novo lipogenesis in the liver contribute to the age-associated increase in hepatic steatosis.•Insulin resistance is the major cause of hepatic lipid accumulation and NAFLD.•GH-IGF-1 axis, Leptin, Adiponectin and inflammation play critical roles in age-related NAFLD.•FGF-21 and mitochondria-derived peptides are potential novel players in the regulation of hepatic lipid accumulation.
Low-alloyed Mg–Li–Er alloys were developed in this study and a bimodal-grained structure was obtained by varying the trace Er content and extrusion temperature. The alloys displayed a good ...strength–ductility synergy, i.e., a tensile yield strength (TYS) of 270 MPa and an elongation (EL) of 19.1%. Microstructural characterization revealed that the formation of numerous submicron Mg24Er5 particles favored a high density of low-angle grain boundaries (LAGBs) inside the deformed grains and inhibited dynamic recrystallization (DRX). The resultant coarse unDRXed grains with a strong basal texture and considerable LAGBs, together with the fine DRXed grains, contributed to the high strength–ductility synergy.
Berberine, an alkaloid derivative from Berberis vulgaris L., has been used extensively in traditional Chinese medicine to treat diarrhea and diabetes, but the underlying mechanisms for treating ...diabetes are not fully understood. Recent studies suggested that berberine has many beneficial biological effects, including anti-inflammation. Because type 1 diabetes is caused by T cell-mediated destruction of β cells and severe islet inflammation, we hypothesized that berberine could ameliorate type 1 diabetes through its immune regulation properties. Here we reported that 2 weeks of oral administration of berberine prevented the progression of type 1 diabetes in half of the NOD mice and decreased Th17 and Th1 cytokine secretion. Berberine suppressed Th17 and Th1 differentiation by reducing the expression of lineage markers. We found that berberine inhibited Th17 differentiation by activating ERK1/2 and inhibited Th1 differentiation by inhibiting p38 MAPK and JNK activation. Berberine down-regulated the activity of STAT1 and STAT4 through the suppression of p38 MAPK and JNK activation, and it controlled the stability of STAT4 through the ubiquitin-proteasome pathway. Our findings indicate that berberine targets MAPK to suppress Th17 and Th1 differentiation in type 1 diabetic NOD mice. This study revealed a novel role of ERK in Th17 differentiation through down-regulation of STAT3 phosphorylation and RORγt expression.
In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in ...reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via the hepatic IGF-1 transgene. We found that liver GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia, and hyperglycemia accompanied with severe insulin resistance and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity and lipid profile in serum and reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, whereas its actions on extrahepatic tissues are mediated by IGF-1.
Acute myocardial infarction (MI) is one of the leading causes of death worldwide. Early identification of ischemia and establishing reperfusion remain cornerstones in the treatment of MI, as ...mortality and morbidity can be significantly reduced by establishing reperfusion to the affected areas. The aim of the current study was to investigate the metabolomic changes in the serum in a swine model of MI induced by ischemia and reperfusion (I/R) injury, and to identify circulating metabolomic biomarkers for myocardial injury at different phases. Female Yucatan minipigs were subjected to 60 min of ischemia followed by reperfusion, and serum samples were collected at baseline, 60 min of ischemia, 4 h of reperfusion, and 24 h of reperfusion. Circulating metabolites were analyzed using an untargeted metabolomic approach. A bioinformatic approach revealed that serum metabolites show distinct profiles during ischemia and during early and late reperfusion. Some notable changes during ischemia include accumulation of metabolites that indicate impaired mitochondrial function and N-terminally modified amino acids. Changes in branched-chain amino-acid metabolites were noted during early reperfusion, while bile acid pathway derivatives and intermediates predominated in the late reperfusion phases. This indicates a potential for such an approach toward identification of the distinct phases of ischemia and reperfusion in clinical situations.
Aging is associated with a decline in mitochondrial function which may contribute to age-related diseases such as neurodegeneration, cancer, and cardiovascular diseases. Recently, mitochondrial ...Complex II has emerged as an important player in the aging process. Mitochondrial Complex II converts succinate to fumarate and plays an essential role in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). The dysfunction of Complex II not only limits mitochondrial energy production; it may also promote oxidative stress, contributing, over time, to cellular damage, aging, and disease. Intriguingly, succinate, the substrate for Complex II which accumulates during mitochondrial dysfunction, has been shown to have widespread effects as a signaling molecule. Here, we review recent advances related to understanding the function of Complex II, succinate signaling, and their combined roles in aging and aging-related diseases.
The molecular mechanisms involved in the development of obesity and related complications remain unclear. Here, we report that obese mice and human subjects have increased activity of neutrophil ...elastase (NE) and decreased serum levels of the NE inhibitor α1-antitrypsin (A1AT, SerpinA1). NE null (Ela2−/−) mice and A1AT transgenic mice were resistant to high-fat diet (HFD)-induced body weight gain, insulin resistance, inflammation, and fatty liver. NE inhibitor GW311616A reversed insulin resistance and body weight gain in HFD-fed mice. Ela2−/− mice also augmented circulating high molecular weight (HMW) adiponectin levels, phosphorylation of AMP-activated protein kinase (AMPK), and fatty acid oxidation (FAO) in the liver and brown adipose tissue (BAT) and uncoupling protein (UCP1) levels in the BAT. These data suggest that the A1AT-NE system regulates AMPK signaling, FAO, and energy expenditure. The imbalance between A1AT and NE contributes to the development of obesity and related inflammation, insulin resistance, and liver steatosis.
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► Obese men and mice have decreased serum A1AT levels and increased NE activity ► Neutrophil infiltration and NE deposition occur in adipose tissue from HFD-fed mice ► NE−/− and A1AT Tg mice have reduced HFD-induced insulin resistance and inflammation ► NE deletion increases AMPK signaling and fatty acid oxidation in liver and BAT
Aging is a risk factor for impaired glucose tolerance and diabetes. Of the reported 25.8 million Americans estimated to have diabetes, 26.9% are over the age of 65. In certain ethnic groups, the ...proportion is even higher; almost 1 in 3 older Hispanics and African Americans and 3 out of 4 Pima Indian elders have diabetes. As per the NHANES III (Third National Health and Nutrition Examination) survey, the percentage of physician-diagnosed diabetes increased from 3.9% in middle-aged adults (40–49 years) to 13.2% in elderly adults (≥75 years). The higher incidence of diabetes is especially alarming considering that diabetes in itself increases the risk for multiple other age-related diseases such as cancer, stroke, cardiovascular diseases, Parkinson’s disease, and Alzheimer’s disease (AD). In this review, we summarize the current evidence on how aging affects pancreatic β cell function, β cell mass, insulin secretion and insulin sensitivity. We also review the effects of aging on the relationship between insulin sensitivity and insulin secretion. Understanding the mechanisms that lead to impaired glucose homeostasis and T2D in the elderly will lead to development of novel treatments that will prevent or delay diabetes, substantially improve quality of life and ultimately increase overall life span.
Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in liver, is prevalent in obesity. Genetic factors that link obesity to NAFLD remain obscure. Apolipoprotein C3 ...(APOC3) is a lipid-binding protein with a pivotal role in triglyceride metabolism. Humans with APOC3 gain-of-function mutations and mice with APOC3 overproduction are associated with hypertriglyceridemia. Nonetheless, it remains controversial whether APOC3 is culpable for diet-induced NAFLD. To address this fundamental issue, we fed APOC3-transgenic and wild-type littermates a high fructose diet or high fat diet, followed by determination of the effect of APOC3 on hepatic lipid metabolism and inflammation and the progression of NAFLD. To gain mechanistic insight into NAFLD, we determined the impact of APOC3 on hepatic triglyceride synthesis and secretion versus fatty acid oxidation. APOC3-transgenic mice were hypertriglyceridemic, culminating in marked elevation of triglycerides, cholesterols, and non-esterified fatty acids in plasma. Despite the prevailing hypertriglyceridemia, APOC3-transgenic mice, relative to wild-type littermates, had similar weight gain and hepatic lipid content without alterations in hepatic expression of key genes involved in triglyceride synthesis and secretion and fatty acid oxidation. APOC3-transgenic and wild-type mice had similar Kupffer cell content without alterations in hepatic expression of pro- and anti-inflammatory cytokines. APOC3 neither exacerbated diet-induced adiposity nor aggravated the degree of steatosis in high fructose or high fat-fed APOC3-transgenic mice. These effects ensued independently of weight gain even after 10-month high fat feeding. We concluded that APOC3, whose dysregulation is liable for hypertriglyceridemia, is not a predisposing factor for linking overnutrition to NAFLD in obesity.
MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc+/− mice are healthier and longer-lived than ...control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. “MycKO” mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc.
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•Postnatal body-wide deletion of the Myc gene in mice causes premature aging•“MycKO” mice dysregulate numerous genes involved in aging, senescence, and cancer•MycKO mice live longer and have a low lifetime cancer incidence•Normal aging in mice and humans is associated with Myc downregulation
Wang et al. show that the postnatal elimination of Myc causes premature aging and the deterioration of age-sensitive functions. Yet, these mice have extended lifespans and a reduced cancer incidence. Gradual Myc downregulation accompanies normal aging in many tissues. Thus, the strong relationship between aging and cancer can be severed by eliminating a single gene.
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