Aging increases the susceptibility of hepatic inflammation, liver fibrosis and aging in response to high-fat diet in mice

Abstract

We aimed to investigate whether aging increases the susceptibility of hepatic and renal inflammation or fibrosis in response to high-fat diet (HFD) and explore the underlying genetic alterations. Middle (10 months old) and old (20 months old) aged, male C57BL/6N mice were fed either a low-fat diet (4 % fat) or HFD (60 % fat) for 4 months. Young (3 months old) aged mice were included as control group. HFDinduced liver and kidney injuries were analyzed by serum and urine assay, histologic staining, immunohistochemistry, and reverse-transcription real-time quantitative polymerase chain reaction. Total RNA sequencing with next-generation technology was done with RNA extracted from liver tissues. With HFD feeding, aged was associated with higher serum alanine aminotransferase levels, marked infiltration of hepatic macrophages, and increased expression of inflammatory cytokines (MCP1, TNF-α, IL-1β, IL-6, IL-12, IL-17A). Importantly, aged mice showed more advanced hepatic fibrosis and increased expression of fibrogenic markers (Col-I-α1, αSMA, TGF-β1, TGF-β2, TGFβRII, PDGF, PDGFRβII, TIMP1) in response to HFD. Aged mice fed on HFD also showed increased oxidative stress and TLR4 expression. In the total RNA seq and gene ontology analysis of liver, old-aged HFD group showed significant up-regulation of genes linked to innate immune response, immune response, defense response, inflammatory response compared to middle-aged HFD group. Meanwhile, aging and HFD feeding showed significant increase in glomerular size and mesangial area, higher urine albumin/creatinine ratio, and advanced renal inflammation or fibrosis. However, the difference of HFD-induced renal injury between oldaged group and middle-aged group was not significant. The susceptibility of hepatic fibrosis as well as hepatic inflammation in response to HFD was significantly increased with aging. In addition, aging was associated with glomerular alterations and increased renal inflammation or fibrosis, while the differential effect of aging AGE (2016) 38:291-302

Resolution of organ fibrosis

“…It is presently unclear how the specific cell fate of myofibroblasts in a given context is determined, and understanding this aspect will be a significant advance. Accumulating evidence indicates that autophagy, a cellular pathway of organelle and protein degradation, can Since mammalian aging is associated with reduced tissue regeneration (150) and increased risk and severity of fibrotic diseases (151,152), targeting molecular alterations associated with aging may lead to reversal of persistent fibrosis in some instances (109).…”

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

“…It has been reported that aged mice are more susceptible to hepatocellular injury, inflammation, and liver fibrosis after high-fat diet feeding. This, is partly due to the sensitization to the Fas death pathway, increased M1 macrophage polarization, and increased innate immune responses [10, 11]. Moreover, accumulating evidence suggests that aged liver is more susceptible to injury due to alcohol abuse [12], which may be due to many mechanisms such as alterations to ethanol metabolism, microsomal ethanol oxidation, CYP2E1, and microsomal activity, and reduction of hepatic mitochondrial functions in the aged liver [13–16].…”

Bioactive Peptide Improves Diet-Induced Hepatic Fat Deposition and Hepatocyte Proinflammatory Response in SAMP8 Ageing Mice

“…Aging and high-fat hypernutrition are known as major risk factors for various systemic and organ-specific disorders, including nonalcoholic fatty liver disease (NAFLD) [1]. These combined factors may promote excess fat deposition in liver or steatosis in more than 5% of hepatic parenchyma, in the context of little amount of alcohol consumption and in absence of existing hepatic pathologies [2].…”