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ObjectiveThe colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults.DesignTo investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults.ResultsPropionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group.ConclusionsThese data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans.Trial registration numberNCT00750438.

•Chronic kidney disease in people with diabetes is often a microvascular complication of diabetes.•Consider an alternate diagnosis if there is good glycaemic control with no other complications, there is an active urine sediment, a rapid decline in eGFR or systemic manifestations of other conditions.•Once diabetic kidney disease (DKD) is diagnosed, use the five-finger rule to enable people to have the standard pillars of care.•Empower the person with DKD by providing access to relevant resources.•Highlight the sick day rules for people with DKD and ensure that if medications are stopped due to intercurrent illness, there is a clear plan to restart these on recovery. Diabetic kidney disease (DKD) management has become increasingly complex. For non-specialists in diabetes or kidney disease, there are some basic standards of care that apply to all people with DKD. These include blood glucose optimisation, blood pressure management, renin–angiotensin–aldosterone system inhibitors (RAASi), lipid management and smoking cessation. There are also risk prediction tools, such as the Kidney Failure Risk Equation, that can be used to guide management and referral to specialist care. This article provides a broad overview of DKD and signposts the reader to useful resources for people with DKD.

Liver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. Understanding the mechanisms leading to functional reprogramming of macrophages in the tumor microenvironment (TME) will benefit cancer immunotherapy. Herein, we find that the scavenger receptor CD36 is upregulated in metastasis-associated macrophages (MAMs) and deletion of CD36 in MAMs attenuates liver metastasis in mice. MAMs contain more lipid droplets and have the unique capability in engulfing tumor cell-derived long-chain fatty acids, which are carried by extracellular vesicles. The lipid-enriched vesicles are preferentially partitioned into macrophages via CD36, that fuel macrophages and trigger their tumor-promoting activities. In patients with liver metastases, high expression of CD36 correlates with protumoral M2-type MAMs infiltration, creating a highly immunosuppressive TME. Collectively, our findings uncover a mechanism by which tumor cells metabolically interact with macrophages in TME, and suggest a therapeutic potential of targeting CD36 as immunotherapy for liver metastasis. Macrophage-mediated immune suppression contributes to poor outcome in liver metastasis. Here the authors show that CD36-expressing metastasis associated macrophages engulf tumor cell-derived extracellular vesicles enriched in long-chain fatty acids, acquiring a pro-tumorigenic phenotype in a preclinical liver metastasis model.

The way in which the composition of the diet may affect appetite, food intake and body weight is now receiving considerable attention in a bid to halt the global year-on-year rise in obesity prevalence. Epidemiological evidence suggests that populations who follow a fibre-rich, traditional diet are likely to have a lower body weight and improved metabolic parameters than their Western-diet counterparts. The colonic effects of fibre, and more specifically the SCFA that the fermentation process produces, may play a role in maintaining energy homeostasis via their action on the G-coupled protein receptor free fatty acid receptor 2 (FFA2; formerly GPR43). In the present review, we summarise the evidence for and against the role of FFA2 in energy homeostasis circuits and the possible ways that these could be exploited therapeutically. We also propose that the decline in fibre content of the diet since the Industrial Revolution, particularly fermentable fractions, may have resulted in the FFA2-mediated circuits being under-utilised and hence play a role in the current obesity epidemic.

Key Points CD36 is a multifunctional receptor for long-chain fatty acids, oxidized lipids, advanced oxidation protein products, thrombospondin and advanced glycation end products CD36 is expressed in a wide variety of kidney cells such as proximal tubular epithelial cells, mesangial cells, podocytes, monocytes and macrophages The expression and intracellular location of CD36 are regulated by multiple ligands with roles in gene transcription and post-translational modifications CD36 is involved in lipid accumulation, inflammation, energy reprograming, apoptosis and kidney fibrosis through activation of Toll-like receptors, Na + /K + ATPase, the NLRP3 inflammasome, PKC-NAPDH oxidase, Scr/Lyn/Fyn and mitogen-activated protein kinases, and TGF-β signalling pathways The levels of circulating soluble CD36 correlate with tissue CD36 expression and could be a biomarker for progression of chronic kidney disease Experimental studies have demonstrated that blockade or knockout of CD36 can prevent kidney injury, suggesting that CD36 could be a novel therapeutic target for the prevention of kidney fibrosis CD36 has important roles in lipid homeostasis, metabolic inflammation, reprogramming of energy metabolism, apoptosis and kidney fibrosis. Here, the authors discuss these roles as well as the regulation and post-translational modification of CD36 and its potential as a biomarker and a therapeutic target for kidney disease. CD36 (also known as scavenger receptor B2) is a multifunctional receptor that mediates the binding and cellular uptake of long-chain fatty acids, oxidized lipids and phospholipids, advanced oxidation protein products, thrombospondin and advanced glycation end products, and has roles in lipid accumulation, inflammatory signalling, energy reprogramming, apoptosis and kidney fibrosis. Renal CD36 is mainly expressed in tubular epithelial cells, podocytes and mesangial cells, and is markedly upregulated in the setting of chronic kidney disease (CKD). As fatty acids are the preferred energy source for proximal tubule cells, a reduction in fatty acid oxidation in CKD affects kidney lipid metabolism by disrupting the balance between fatty acid synthesis, uptake and consumption. The outcome is intracellular lipid accumulation, which has an important role in the pathogenesis of kidney fibrosis. In experimental models, antagonist blockade or genetic knockout of CD36 prevents kidney injury, suggesting that CD36 could be a novel target for therapy. Here, we discuss the regulation and post-translational modification of CD36, its role in renal pathophysiology and its potential as a biomarker and as a therapeutic target for the prevention of kidney fibrosis.

People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.

Background Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors are highly warranted. Methods We analysed a group of 78 HCC patients who received sorafenib treatment after liver resection surgery. The expression of SCAP and its correlation with sorafenib resistance in HCC clinical samples were determined by immunohistochemical analyses. Overexpression and knockdown approaches in vitro were used to characterize the functional roles of SCAP in regulating sorafenib resistance. The effects of SCAP inhibition in HCC cell lines were analysed in proliferation, apoptosis, and colony formation assays. Autophagic regulation by SCAP was assessed by immunoblotting, immunofluorescence and immunoprecipitation assays. The combinatorial effect of a SCAP inhibitor and sorafenib was tested using nude mice. Results Hypercholesterolemia was associated with sorafenib resistance in HCC treatment. The degree of sorafenib resistance was correlated with the expression of the cholesterol sensor SCAP and consequent deposition of cholesterol. SCAP is overexpressed in HCC tissues and hepatocellular carcinoma cell lines with sorafenib resistance, while SCAP inhibition could improve sorafenib sensitivity in sorafenib-resistant HCC cells. Furthermore, we found that SCAP-mediated sorafenib resistance was related to decreased autophagy, which was connected to decreased AMPK activity. A clinically significant finding was that lycorine, a specific SCAP inhibitor, could reverse acquired resistance to sorafenib in vitro and in vivo. Conclusions SCAP contributes to sorafenib resistance through AMPK-mediated autophagic regulation. The combination of sorafenib and SCAP targeted therapy provides a novel personalized treatment to enhance sensitivity in sorafenib-resistant HCC.

According to the 'lipid nephrotoxicity hypothesis', hyperlipidemia resulting from physiological compensatory synthesis of lipoproteins in response to urinary loss of albumin can itself cause or aggravate glomerular and tubulointerstitial disease. Ruan and colleagues discuss the evidence on the mutual influence that dysregulation of lipid homeostasis and renal disease exert on each other and how such evidence confirms, qualifies and modifies the lipid nephrotoxicity hypothesis. When the 'lipid nephrotoxicity hypothesis' was proposed in 1982, it brought together several disparate experimental findings in hyperlipidemia and renal disease to suggest that concomitant hyperlipidemia and proteinuria would cause self-perpetuating renal disease once the initial glomerular insult was no longer present. This process would be analogous to atherosclerosis. Since 1982, increasing evidence has supported the hypothesis that lipid abnormalities contribute to both atherosclerosis and glomerulosclerosis. In this Review, we discuss research developments that are relevant to the lipid nephrotoxicity hypothesis. We describe how inflammatory stress accompanying chronic kidney disease modifies lipid homeostasis by increasing cholesterol uptake mediated by lipoprotein receptors, inhibiting cholesterol efflux mediated by the ATP-binding cassette transporter 1 and impairing cholesterol synthesis in peripheral cells. As a result of these events, cholesterol relocates to and accumulates in renal, vascular, hepatic and possibly other tissues. The combination of increased cellular cholesterol influx and reduced efflux causes injury in some tissues and lowers the plasma cholesterol level. In addition, inflammatory stress causes a degree of statin resistance via unknown mechanisms. These phenomena alter traditional understanding of the pathogenesis of lipid-mediated renal and vascular injury and could influence the clinical evaluation of renal and cardiovascular risk and the role of lipid-lowering treatment in affected patients. Key Points Atherogenic dyslipidemia in association with proteinuria can occur early in primary kidney disease, when the measured glomerular filtration rate is within the healthy range Many animal models and clinical studies suggest that dyslipidemia contributes to progressive renal disease, as was originally suggested by the 'lipid nephrotoxicity hypothesis' Renal pathophysiological changes driven by atherogenic dyslipidemia include inflammatory stress, oxidative stress, endoplasmic reticulum stress, endothelial dysfunction and activation of the renin–angiotensin system Inflammatory stress modifies lipid homeostasis through changes in lipoprotein composition and in cholesterol distribution among plasma, tissues and cellular organelles Emerging evidence from clinical trials suggests that statins reduce proteinuria and possibly the rate of kidney function loss in patients with renal disease and dyslipidemia Some experimental evidence suggests that inflammatory stress might cause 'statin resistance' and reduced the effectiveness of statin treatment

Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. Methods In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.